Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target




Cancer, Nuclear shuttling, Y-box binding protein 1


Y-box binding protein 1 (YB-1) is an imperative biomarker for the clinical out-come of cancer patients. An overexpression of YB-1 in cancerous and adjoining tissues is an indication of aggressiveness and advanced stages. In normal resting cells, YB-1 is localized in cytoplasm while in stress conditions like cancer, nuclear shuttling of YB-1 takes place. In this review, the clinical importance of YB-1 in different cancers and the mechanism behind YB-1 nuclear shuttling have been discussed in detail. Targeted chemotherapies or molecularly targeted drugs of great importance can target and block specific molecules implicated in tumor growth and progression. YB-1 has been considered as a bonafide oncogene and accumulating evidences show the therapeutic importance of YB-1. Therapeutic strategies targeting YB-1 may improve the survival rate in cancer patients. This review extensively discusses the therapeutic importance of YB-1.



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Author Biographies

Vinoth Prasanna Gunasekaran, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, Tamilnadu

Research Scholar

Kumari Nishi, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, Tamilnadu

Postdoctoral fellow

Vilwanathan Ravikumar, Department of Biochemistry, Bharathidasan University, Tiruchirappalli, Tamilnadu

Assistant Professor

Ganeshan Mathan, Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, Tamilnadu

Assistant Professor


Adhami VM, Khan MI, Lall RK, Siddiqui IA, Syed DN, Sechi M, Dodwad SJ, Mukhtar H. Role of YB-1, a regulator of epithelial to mesenchymal transition, in prostate cancer: Inhibition by a dietary flavonoid fisetin. Cancer Res. 2013; 73: 5551.

Alemany R. Cancer selective adenoviruses. Mol Aspects Med. 2007; 28: 42-58.

Andrade de Oliveira LJ, D'Oliveira A, Melo RC, De Souza EC, Silva CA, Parana R. Association between hepatitis C and hepatocellular carcinoma. J Glob Infect Dis. 2009; 1: 33.

Astanehe A, Finkbeiner MR, Krzywinski M, Fotovati A, Dhillon J, Berquin IM, Mills GB, Marra MA, Dunn SE. MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition. Oncogene 2012; 31: 4434-46.

Bader AG, Vogt PK. Inhibition of protein synthesis by Y-box binding protein 1 blocks oncogenic cell transformation. Mol Cell Biol. 2005; 25: 2095-106.

Baptiste N, Friedlander P, Chen X, Prives C. The proline-rich domain of p53 is required for cooperation with anti-neoplastic agents to promote apoptosis of tumor cells. Oncogene 2002; 21: 9-21.

Basaki Y, Hosoi F, Oda Y, Fotovati A, Maruyama Y, Oie S, Ono M, Izumi H, Kohno K, Sakai K, Shimoyama T. Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells. Oncogene 2007; 26: 2736-46.

Bergmann S, Royer-Pokora B, Fietze E, Jürchott K, Hildebrandt B, Trost D, Leenders F, Claude JC, Theuring F, Bargou R, Dietel M. YB-1 provokes breast cancer through the induction of chromosomal instability that emerges from mitotic failure and centrosome amplification. Cancer Res. 2005; 65: 4078-87.

Berquin IM, Pang B, Dziubinski ML, Scott LM, Chen YQ, Nolan GP, Ethier SP. Y-box-binding protein 1 confers EGF independence to human mammary epithelial cells. Oncogene 2005; 24: 3177-86.

Bhardwaj A, Singh S, Srivastava SK, Arora S, Reed E, Singh AP. Olive polyphenol, hydroxytyrosol, exerts anti-tumor effects in prostate cancer cells by targeting Akt, STAT3 and AR signaling. Cancer Res. 2012; 72: 605.

Blüthgen N, Legewie S, Kielbasa SM, Schramme A, Tchernitsa O, Keil J, Solf A, Vingron M, Schäfer R, Herzel H, Sers C. A systems biological approach suggests that transcriptional feedback regulation by dual?specificity phosphatase 6 shapes extracellular signal?related kinase activity in RAS?transformed fibroblasts. FEBS J 2009; 276: 1024-35.

Bogolyubova IO, Lyabin DN, Bogolyubov DS, Ovchinnikov LP. Immunocytochemical study of YB-1 nuclear distribution in different cell types. Tissue Cell. 2014; 46: 457-61.

Bommert KS, Effenberger M, Leich E, Küspert M, Murphy D, Langer C, Moll R, Janz S, Mottok A, Weissbach S, Rosenwald A. The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival. Leukemia 2013; 27: 441-50.

Bosch FX, Ribes J, Borràs J. Epidemiology of primary liver cancer. Semin Liver Dis. 1999; 19: 271-85.

Byrne AM, Bouchier?Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005; 9: 777-94.

Cai MY, Tong ZT, Zheng F, Liao YJ, Wang Y, Rao HL, Chen YC, Wu QL, Liu YH, Guan XY, Lin MC. EZH2 protein: A promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies. Gut 2011; 60: 967-76.

Cakouros D, Isenmann S, Cooper L, Zannettino A, Anderson P, Glackin C, Gronthos S. Twist-1 induces Ezh2 recruitment regulating histone methylation along the Ink4A/Arf locus in mesenchymal stem cells. Mol Cell Biol. 2012; 32: 1433-41.

Caruz A, Samsom M, Alonso JM, Alcami J, Baleux F, Virelizier JL, Parmentier M, Arenzana-Seisdedos F. Genomic organiza-tion and promoter characterization of human CXCR4 gene. FEBS Lett. 1998; 426: 271-78.

Castellana B, Aasen T, y Cajal SR. Interplay of YB-1 and IL-6 in the acquisition of EMT-like characteristics. Cancer Res. 2014; 74: 1053.

Chatterjee M, Rancso C, Stühmer T, Eckstein N, Andrulis M, Gerecke C, Lorentz H, Royer HD, Bargou RC. The Y-box binding protein YB-1 is associated with progressive disease and mediates survival and drug resistance in multiple myeloma. Blood 2008; 111: 3714-22.

Chen T, Boisvert F-M, Bazett-Jones DP, Richard S. A role for the GSG domain in localizing Sam68 to novel nuclear structures in cancer cell lines. Mol Biol Cell. 1999; 10: 3015-33.

Cheng GZ, Zhang W, Sun M, Wang Q, Coppola D, Mansour M, Xu L, Costanzo C, Cheng JQ, Wang LH. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem. 2008; 283: 14665-73.

Chernukhin IV, Shamsuddin S, Robinson AF, Carne AF, Paul A, El-Kady AI, Lobanenkov VV, Klenova EM. Physical and functional interaction between two pluripotent proteins, the Y-box DNA/RNA-binding factor, YB-1, and the multivalent zinc finger factor, CTCF. J Biol Chem. 2000; 275: 29915-21.

Choi YK, Cho SG, Choi HS, Woo SM, Yun YJ, Shin YC, Ko SG. JNK1/2 activation by an extract from the roots of Morus alba L. reduces the viability of multidrug-resistant MCF-7/Dox cells by inhibiting YB-1-dependent MDR1 expression. Evid Based Complement Alternat Med. 2013; 2013: 741985.

Coles LS, Lambrusco L, Burrows J, Hunter J, Diamond P, Bert AG, Vadas MA, Goodall GJ. Phosphorylation of cold shock domain/Y?box proteins by ERK2 and GSK3? and repression of the human VEGF promoter. FEBS Lett. 2005; 579: 5372-78.

Cybulski M, Jarosz B, Nowakowski A, Jeleniewicz W, Kutarska E, Bednarek W, Stepulak A. Cyclin A Correlates with YB1, Progression and resistance to chemotherapy in human epithelial ovarian cancer. Anticancer Res. 2015; 35: 1715-21.

Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P. Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK. J Biol Chem. 1998; 273: 1496-505.

Davies AH, Dunn SE. YB-1 drives preneoplastic progression: Insight into opportunities for cancer prevention. Oncotarget 2011; 2: 40106.

Davies AH, Reipas KM, Pambid MR, Berns R, Stratford AL, Fotovati A, Firmino N, Astanehe A, Hu K, Maxwell C, Mills GB. YB?1 Transforms human mammary epithelial cells through chromatin remodeling leading to the development of basal?like breast cancer. Stem Cells. 2014; 32 :1437-50.

Denegri M, Chiodi I, Corioni M, Cobianchi F, Riva S, Biamonti G. Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors. Mol Biol Cell. 2001; 12: 3502-14.

De Santis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014; 64: 252-71

Didier DK, Schiffenbauer J, Woulfe SL, Zacheis M, Schwartz BD. Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class II Y box. Proc Natl Acad Sci. 1988; 85: 7322-26.

Docquier F, Farrar D, D'Arcy V, Chernukhin I, Robinson AF, Loukinov D, Vatolin S, Pack S, Mackay A, Harris RA, Dorricott H. Heightened expression of CTCF in breast cancer cells is associated with resistance to apoptosis. Cancer Res. 2005; 65: 5112-22.

Dong X, Yu C, Shynlova O, Challis JR, Rennie PS, Lye SJ: p54nrb is a transcriptional corepressor of the progesterone receptor that modulates transcription of the labor-associated gene, connexin 43 (Gja1). Mol Endocrinol. 2009; 23: 1147-60.

Evdokimova V, Ruzanov P, Anglesio MS, Sorokin AV, Ovchinnikov LP, Buckley J, Triche TJ, Sonenberg N, Sorensen PH. Akt-mediated YB-1 phosphorylation activates translation of silent mRNA species. Mol Cell Biol. 2006; 26: 277-92.

Evdokimova V, Tognon C, Ng T, Ruzanov P, Melnyk N, Fink D, Sorokin A, Ovchinnikov LP, Davicioni E, Triche TJ, Sorensen PH. Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell. 2009; 15: 402-15.

Fatima G, Mathan G, Kumar V. The HBx protein of hepatitis B virus regulates the expression, intracellular distribution and functions of ribosomal protein S27a. J Gen Virol. 2012; 93: 706-15.

Faury D, Nantel A, Dunn SE, Guiot MC, Haque T, Hauser P, Garami M, Bognár L, Hanzély Z, Liberski PP, Lopez-Aguilar E. Molecular profiling identifies prognostic subgroups of pediatric glioblastoma and shows increased YB-1 expression in tumors. J Clin Oncol. 2007; 25: 1196-208.

Feng T, Dzieran J, Gu X, Marhenke S, Vogel A, Machida K, Weiss TS, Ruemmele P, Kollmar O, Hoffmann P, Grässer F. Smad7 regulates compensatory hepatocyte proliferation in damaged mouse liver and positively relates to better clinical outcome in human hepatocellular carcinoma. Clin Sci (Lond). 2015; 128: 761-74.

Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol. 1996; 16: 2802-13.

Filippova GN, Lindblom A, Meincke LJ, Klenova EM, Neiman PE, Collins SJ, Doggett NA, Lobanenkov VV. A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16 q 22. 1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers. Genes Chromosom Cancer. 1998; 22: 26-36.

Finkbeiner MR, Astanehe A, To K, Fotovati A, Davies AH, Zhao Y, Jiang H, Stratford AL, Shadeo A, Boccaccio C, Comoglio P. Profiling YB-1 target genes uncovers a new mechanism for MET receptor regulation in normal and malignant human mammary cells. Oncogene 2009; 28: 1421-31.

Fotovati A, Abu-Ali S, Wang PS, Deleyrolle LP, Lee C, Triscott J, Chen JY, Franciosi S, Nakamura Y, Sugita Y, Uchiumi T. YB-1 bridges neural stem cells and brain tumorinitiating cells via its roles in differentiation and cell growth. Cancer Res. 2011; 71: 5569-78.

Fujii T, Seki N, Namoto-Matsubayashi R, Takahashi H, Inoue Y, Toh U, Kage M, Shirouzu K. YB-1 prevents apoptosis via the mTOR/STAT3 pathway in HER-2-overexpressing breast cancer cells. Future Med. 2009; 5: 153-56.

Funakoshi T, Kobayashi S, Ohashi S, Sato TA, Anzai K. Isolation and characterization of brain Y-box protein: Developmentally regulated expression, polyribosomal association and dendritic localization. Mol Brain Res. 2003; 118: 1-9.

Gessner C, Woischwill C, Schumacher A, Liebers U, Kuhn H, Stiehl P, Jürchott K, Royer HD, Witt C, Wolff G. Nuclear YB?1 expression as a negative prognostic marker in non-small cell lung cancer. Eur Respir J. 2004; 23: 14-19.

Golubovskaya VM. Focal adhesion kinase as a cancer therapy target. Anticancer Agents Med Chem. 2010; 10: 73541.

Grøndahl-Hansen J, Christensen IJ, Rosenquist C, Brünner N, Mouridsen HT, Danø K, Blichert-Toft M. High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res. 1993; 53: 2513-21.

Gunasekaran VP, Ganeshan M. Inverse correlation of ribosomal protein S27A and multifunctional protein YB-1 in hepatocellular carcinoma. Clin Biochem. 2014; 47: 1262-64.

Guo T, Yu Y, Yip GW, Baeg GH, Thike AA, Lim TK, Tan PH, Matsumoto K, Bay BH. Y?box binding protein 1 is correlated with lymph node metastasis in intestinal?type gastric cancer. Histopathology 2015; 66: 491-99.

Guo TT, Yu YN, Yip C, Wai G, Matsumoto K, Bay BH. Silencing the YB?1 gene inhibits cell migration in gastric Cancer in vitro. Anat Rec (Hoboken). 2013; 296: 891-98.

Ha B, Lee EB, Cui J, Kim Y, Jang HH. YB-1 overexpression promotes a TGF-?1-induced epithelialmesenchymal tran-sition via Akt activation. Biochem Biophys Res Commun. 2015; 458: 347-51.

Habibi G, Leung S, Law JH, Gelmon K, Masoudi H, Turbin D, Pollak M, Nielsen TO, Huntsman D, Dunn SE. Redefining prognostic factors for breast cancer: YB-1 is a stronger predictor of relapse and disease-specific survival than estrogen receptor or HER-2 across all tumor subtypes. Breast Cancer Res. 2008; 10: R86.

Harada M, Kotake Y, Ohhata T, Kitagawa K, Niida H, Matsuura S, Funai K, Sugimura H, Suda T, Kitagawa M. YB?1 promotes transcription of cyclin D1 in human non?small?cell lung cancers. Genes Cells. 2014; 19: 504-16.

Higashi K, Tomigahara Y, Shiraki H, Miyata K, Mikami T, Kimura T, Moro T, Inagaki Y, Kaneko H. A novel small compound that promotes nuclear translocation of YB-1 ameliorates experimental hepatic fibrosis in mice. J Biol Chem. 2011; 286: 4485-92.

Holm PS, Bergmann S, Jürchott K, Lage H, Brand K, Ladhoff A, Mantwill K, Curiel DT, Dobbelstein M, Dietel M, Gänsbacher B. YB-1 relocates to the nucleus in adenovirus-infected cells and facilitates viral replication by inducing E2 gene expression through the E2 late promoter. J Biol Chem. 2002; 277: 10427-34.

Horwitz EM, Maloney KA, Ley TJ. A human protein containing a" cold shock" domain binds specifically to H-DNA up-stream from the human gamma-globin genes. J Biol Chem. 1994; 269: 14130-39.

Hunt C, Morimoto RI. Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci. 1985; 82: 6455-59.

Ichimura K, Schmidt EE, Goike HM, Collins VP. Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. Oncogene 1996; 13: 1065-72.

Ito Y, Yoshida H, Shibahara K, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsuzuka F, Uchimi T. Y?box binding protein expression in thyroid neoplasms: Its linkage with anaplastic transformation. Pathol Int. 2003; 53: 429-33.

Jensen CJ, Buch M-B, Krag TO, Hemmings BA, Gammeltoft S, Frodin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999; 274: 27168-76.

Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293: 1074.

Jürchott K, Bergmann S, Stein U, Walther W, Janz M, Manni I, Piaggio G, Fietze E, Dietel M, Royer HD. YB-1 as a cell cycle-regulated transcription factor facilitating cyclin A and cyclin B1 gene expression. J Biol Chem. 2003; 278: 27988-96.

Jürchott K, Kuban RJ, Krech T, Blüthgen N, Stein U, Walther W, Friese C, Kie?basa SM, Ungethüm U, Lund P, Knösel T. Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells. PLoS Genet. 2010; 6: e1001231.

Jurica MS, Licklider LJ, Gygi SR, Grigorieff N, Moore MJ. Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis. RNA 2002; 8: 426-39.

Kamura T, Yahata H, Amada S, Ogawa S, Sonoda T, Kobayashi H, Mitsumoto M, Kohno K, Kuwano M, Nakano H. Is nuclear expression of Y box?binding protein?1 a new prognostic factor in ovarian serous adenocarcinoma? Cancer. 1999; 85: 2450-54.

Kang Y, Hu W, Ivan C, Dalton HJ, Miyake T, Pecot CV, Zand B, Liu T, Huang J, Jennings NB, Rupaimoole R. Role of focal adhesion kinase in regulating YB1mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst. 2013; djt210.

Kanie T, Onoyama I, Matsumoto A, Yamada M, Nakatsumi H, Tateishi Y, Yamamura S, Tsunematsu R, Matsumoto M, Nakayama KI. Genetic reevaluation of the role of F-box proteins in cyclin D1 degradation. Mol Cell Biol. 2012; 32: 590-605.

Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: Mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 2013; 32: 501-11.

Khan MI, Adhami VM, Lall RK, Sechi M, Joshi DC, Haidar OM, Syed DN, Siddiqui IA, Chiu SY, Mukhtar H. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget 2014; 5: 2462-74.

Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, Oh YT, Kim H, Rheey J, Nakano I, Lee C. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013; 23: 839-52.

Kim ER, Selyutina AA, Buldakov IA, Evdokimova V, Ovchinnikov LP, Sorokin AV. The proteolytic YB-1 fragment interacts with DNA repair machinery and enhances survival during DNA damaging stress. Cell Cycle. 2013; 12: 3791-803.

Kloks CP, Spronk CA, Lasonder E, Hoffmann A, Vuister GW, Grzesiek S, Hilbers CW. The solution structure and DNA-binding properties of the cold shock domain of the human Y-box protein YB-1. J Mol Biol. 2002; 316: 317-26.

Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M. The pleiotropic functions of the y-box-binding protein, YB-1. Bioessays. 2003; 25: 691-98.

Koike K, Uchiumi T, Ohga T, Toh S, Wada M, Kohno K, Kuwano M. Nuclear translocation of the Y-box binding protein by ultraviolet irradiation. FEBS Lett. 1997; 417: 390-94.

Kryczek I, Lange A, Mottram P, Alvarez X, Cheng P, Hogan M, Moons L, Wei S, Zou L, Machelon V, Emilie D. CXCL12 and vascular endothelial growth factor synergistically induce neoangiogenesis in human ovarian cancers. Cancer Res. 2005; 65: 465-72.

Kuo MT. Redox regulation of multidrug resistance in cancer chemotherapy: Molecular mechanisms and therapeutic opportunities. Anti-oxid Redox Signal. 2009; 11: 99-133.

Lakhtakia R, Kumar V, Reddi H, Mathur M, Dattagupta S, Panda SK. Hepatocellular carcinoma in a hepatitis B x transgenic mouse model: A sequential pathological evaluation. J Gastroenterol Hepatol. 2003; 18: 80-91.

Lee C, Dhillon J, Wang MY, Gao Y, Hu K, Park E, Astanehe A, Hung MC, Eirew P, Eaves CJ, Dunn SE. Targeting YB-1 in HER-2 overexpressing breast cancer cells induces apoptosis via the mTOR/STAT3 pathway and suppresses tumor growth in mice. Cancer Res. 2008; 68: 8661-66.

Lenz J, Okenquist SA, LoSardo JE, Hamilton KK, Doetsch PW. Identification of a mammalian nuclear factor and human cDNA-encoded proteins that recognize DNA containing apurinic sites. Proc Nat Acad Sci. 1990; 87: 3396-400.

Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potentials for cancer prevention and therapy. Curr Cancer Drug Targets. 2008; 8: 63446.

Lorsch JR. RNA chaperones exist and DEAD box proteins get a life. Cell 2002; 109: 797-800.

Lovett DH, Cheng S, Cape L, Pollock AS, Mertens PR. YB-1 alters MT1-MMP trafficking and stimulates MCF-7 breast tumor invasion and metastasis. Biochem Biophys Res Commun. 2010; 398: 482-88.

Makino Y, Ohga T, Toh S, Koike K, Okumura K, Wada M, Kuwano M, Kohno K. Structural and functional analysis of the human Y-box binding protein (YB-1) gene promoter. Nucleic Acids Res. 1996; 24: 1873-38.

Mantwill K, Naumann U, Seznec J, Girbinger V, Lage H, Surowiak P, Beier D, Mittelbronn M, Schlegel J, Holm PS. YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells. J Transl Med. 2013; 11: 216.

Mertens PR, Alfonso-Jaume MA, Steinmann K, Lovett DH. A synergistic interaction of transcription factors AP2 and YB-1 regulates gelatinase A enhancer-dependent transcription. J Biol Chem. 1998; 273: 32957-65.

Minich WB, Maidebura IP, Ovchinnikov LP. Purification and characterization of the major 50?kDa repressor protein from cytoplasmic mRNP of rabbit reticulocytes. Eur J Biochem. 1993; 212: 633-38.

Morel C, Kayibanda B, Scherrer K. Proteins associated with globin messenger RNA in avian erythroblasts: Isolation and comparison with the proteins bound to nuclear messenger?likie RNA. FEBS lett. 1971; 18: 84-88.

Mrugala MM. Advances and challenges in the treatment of glioblastoma: A clinicians perspective. Discov Med. 2013; 15: 221-30.

Mubeen M, Kini SG. A review on the design and development of EGFR tyrosine kinase inhibitors in cancer therapy. Int J Therap Appl. 2012; 5: 29-37.

Müller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O'Connor MB, Kingston RE, Simon JA. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 2002; 111: 197-208.

Niu G, Chen X. Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets. 2010; 11: 1000-17.

Oda Y, Ohishi Y, Basaki Y, Kobayashi H, Hirakawa T, Wake N, Ono M, Nishio K, Kuwano M, Tsuneyoshi M. Prognostic implications of the nuclear localization of Y?box?binding protein?1 and CXCR4 expression in ovarian cancer: Their correlation with activated Akt, LRP/MVP and P?glycoprotein expression. Cancer Sci. 2007; 98: 1020-26.

Oda Y, Ohishi Y, Saito T, Hinoshita E, Uchiumi T, Kinukawa N, Iwamoto Y, Kohno K, Kuwano M, Tsuneyoshi M. Nuclear expression of Y?box?binding protein?1 correlates with P?glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma. J Pathol. 2003; 199: 251-58.

Ohga T, Koike K, Ono M, Makino Y, Itagaki Y, Tanimoto M, Kuwano M, Kohno K. Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light. Cancer Res. 1996; 56: 4224-28.

Oki E, Kakeji Y, Tokunaga E, Yoshida R, Egashira A, Sadanaga N, Morita M, Taguchi K, Kuwano M, Maehara Y. Akt-mediated YB-1 phosphorylation induces resistance for chemotherapy of gastric cancer. J Clin Oncol (meeting abstract). 2007; 25: 4554.

Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu ET, Cance WG. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. Cancer Res. 1995; 55: 275255.

Ozer J, Chalkley R, Sealy L. Characterization of rat pseudogenes for enhancer factor I subunit A: Ripping provides clues to the evolution of the EFIAdbpB/YB-1 multigene family. Gene 1993; 133: 187-95.

Parato KA, Senger D, Forsyth PA, Bell JC. Recent progress in the battle between oncolytic viruses and tumours. Nat Rev Cancer 2005; 5: 965-76.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55: 74-108.

Petrakis TG, Vougas K, Gorgoulis VG. Cdc6: A multi-functional molecular switch with critical role in carcinogenesis. Transcription. 2012; 3: 124-9.

Raffetseder U, Frye B, Rauen T, Jürchott K, Royer HD, Jansen PL, Mertens PR. Splicing factor SRp30c interaction with Y-box protein-1 confers nuclear YB-1 shuttling and alternative splice site selection. J Biol Chem. 2003; 278: 18241-48.

Ramli SZ, Sundaram A, Samsuddin NA, Malin J, Haspani M, Balakrishnan V, Hassan NN, Shamsuddin S. Expression analysis of transcription factors CTCF (CCCTC-binding factor), BORIS (Brother of the regulator imprinted sites) and YB-1 (Y-box binding factor 1) in osteosarcoma and glioma cell lines: Physical Interaction of CTCF~YB-1 in vivo. Biomed Res. 2012; 23: 333-42.

Raouf A, Zhao Y, To K, Stingl J, Delaney A, Barbara M, Iscove N, Jones S, McKinney S, Emerman J, Aparicio S, Marra M, Eaves C. Transcriptome analysis of the normal human mammary cell commitment and differentiation process. Cell Stem Cell. 2008; 3: 10918.

Reipas KM, Law JH, Couto N, Islam S, Li Y, Li H, Cherkasov A, Jung K, Cheema AS, Jones SJ, Hassell JA. Luteolin is a novel p90 ribosomal S6 kinase (RSK) inhibitor that suppresses Notch4 signaling by blocking the activation of Y-box binding protein-1 (YB-1). Oncotarget 2013; 4: 329-45.

Sacco E, Hasan MM, Alberghina L, Vanoni M. Comparative analysis of the molecular mechanisms controlling the initiation of chromosomal DNA replication in yeast and in mammalian cells. Biotechnol Adv. 2012; 30: 73-98.

Schittek B, Psenner K, Sauer B, Meier F, Iftner T, Garbe C. The increased Schittek B, Psenner K, Sauer B, Meier F, Iftner T, Garbe C. The increased expression of Y box?binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistance. Int J Cancer. 2007; 120: 2110-18.

Schmid R, Meyer K, Spang R, Schittek B, Bosserhoff AK. YBX1 is a modulator of MIA/CD-RAP-dependent chondrogenesis. PloS one. 2013; 8: e82166.

Shen H, Xu W, Luo W, Zhou L, Yong W, Chen F, Wu C, Chen Q, Han X. Up-regulation of mdr1 gene is related to activation of the MAPK/ERK signal transduction pathway and YB-1 nuclear translocation in B-cell lymphoma. Exp Hematol. 2011; 39: 558-69.

Sheridan CM, Grogan TR, Nguyen HG, Galet C, Rettig MB, Hsieh AC, Ruggero D. YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence. Oncotarget 2015; 6: 7470.

Shibao K, Takano H, Nakayama Y, Okazaki K, Nagata N, Izumi H, Uchiumi T, Kuwano M, Kohno K, Itoh H. Enhanced coexpression of YB?1 and DNA topoisomerase II ? genes in human colorectal carcinomas. Int J Cancer. 1999; 83: 732-37.

Shinichi K, Mattei MG, Fukuda M, Characterization of the gene for dbpA, a family member of the nucleic?acid?binding proteins containing a Cold?Shock domain. Eur J Biochem. 1995; 231: 72-82.

Shiota M, Kashiwagi E, Yokomizo A, Takeuchi A, Dejima T, Song Y, Tatsugami K, Inokuchi J, Uchiumi T, Naito S. Interaction between docetaxel resistance and castration resistance in prostate cancer: Implications of twist1, YB?1, and androgen receptor. Prostate 2013; 73: 1336-44.

Shiota M, Yokomizo A, Itsumi M, Uchiumi T, Tada Y, Song Y, Kashiwagi E, Masubuchi D, Naito S. Twist1 and Y?box?binding protein?1 promote malignant potential in bladder cancer cells. BJU Int. 2011; 108: E142-49.

Shiota M, Yokomizo A, Takeuchi A, Itsumi M, Imada K, Kashiwagi E, Inokuchi J, Tatsugami K, Uchiumi T, Naito S. Inhibition of RSK/YB?1 signaling enhances the anticancer effect of enzalutamide in prostate cancer. Prostate 2014; 74: 959-69.

Sinnberg T, Sauer B, Holm P, Spangler B, Kuphal S, Bosserhoff A, Schittek B. MAPK and PI3K/AKT mediated YB?1 activation promotes melanoma cell proliferation which is counteracted by an autoregulatory loop. Exp Dermatol. 2012; 21: 265-70.

Skarin AT, Dorfman DM. Non?Hodgkin's lymphomas: Current classification and management. CA Cancer J Clin. 1997; 47: 351-72.

Somasekharan SP, El-Naggar A, Leprivier G, Cheng H, Hajee S, Grunewald TG, Zhang F, Ng T, Delattre O, Evdokimova V, Wang Y. YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1. J Cell bio. 2015; 208: 913-29.

Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J. Repeated observation of breast tumor subtypes in independent gene expression data sets. Pro Natl Acad Sci. 2003; 100: 8418-23.

Spitkovsky DD, Royer-Pokora B, Delius H, Kisseljov F, Jenkins NA, Gilbert DJ, Copeland NG, Royer HD. Tissue restricted expression and chromosomal localization of the YB-1 gene encoding a 42kD nuclear CCAAT binding protein. Nucleic Acids Res. 1992; 20: 797-803.

Stoss O, Olbrich M, Hartmann AM, König H, Memmott J, Andreadis A, Stamm S. The STAR/GSG family protein rSLM-2 regulates the selection of alternative splice sites. J Biol Chem. 2001; 276: 8665-73.

Stoss O, Schwaiger FW, Cooper TA, Stamm S. Alternative splicing determines the intracellular localization of the novel nuclear protein Nop30 and its interaction with the splicing factor SRp30c. J Biol Chem. 1999; 274: 10951-62.

Stratford AL, Fry CJ, Desilets C, Davies AH, Cho YY, Li Y, Dong Z, Berquin IM, Roux PP, Dunn SE. Y-box binding protein-1 serine 102 is a down-stream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. Breast Cancer Res. 2008; 10: R99.

Stratford AL, Habibi G, Astanehe A, Jiang H, Hu K, Park E, Shadeo A, Buys TP, Lam W, Pugh T, Marra M. Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res. 2007; 9: R61.

Sullivan NJ, Sasser AK, Axel A, Vesuna F, Raman V, Ramirez N, Oberyszyn TM, Hall BM. Interleukin-6 induces an epithelialmesenchymal transition phenotype in human breast cancer cells. Oncogene 2009; 28: 2940-47.

Sulzmaier FJ, Ramos JW. RSK isoforms in cancer cell invasion and metastasis. Cancer Res. 2013; 73: 6099-105.

Sutherland BW, Kucab J, Wu J, Lee C, Cheang MC, Yorida E, Turbin D, Dedhar S, Nelson C, Pollak M, Grimes HL. Akt phosphorylates the Y-box binding protein 1 at Ser102 located in the cold shock domain and affects the anchorage-independent growth of breast cancer cells. Oncogene 2005; 24: 4281-92.

Suzuki H, Ueda T, Ichikawa T, Ito H. Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer. 2003; 10: 209-16.

Syed DN, Lall RK, Khan M, Mukhtar H. Elevated expression of YB-1 in UVB exposed keratinocytes, human basal and squamous cell carcinomas. J Invest Dermatol. 2014; 134: S36-S36.

Szczuraszek K, HALON A, Materna V, Mazur G, Wrobel T, Kuliczkowski K, Donizy P, Holm PS, Lage H, Surowiak P. Elevated YB-1 expression is a new unfavorable prognostic factor in non-Hodgkin's lymphomas. Anticancer Res. 2011; 31: 2963-70.

Tacke F, Galm O, Kanig N, Yagmur E, Brandt S, Lindquist JA, Eberhardt CS, Raffetseder U, Mertens PR. High prevalence of Y-box protein-1/p18 fragment in plasma of patients with malignancies of different origin. BMC Cancer. 2014; 14: 1.

Tacke F, Kanig N, En-Nia A, Kaehne T, Eberhardt CS, Shpacovitch V, Trautwein C, Mertens PR. Y-box protein-1/p18 fragment identifies malignancies in patients with chronic liver disease. BMC Cancer. 2011; 11: 1.

Takeuchi A, Shiota M, Tatsugami K, Yokomizo A, Kuroiwa K, Dejima T, Tanaka S, Itsumi M, Eto M, Naito S. YB-1 suppression induces STAT3 proteolysis and sensitizes renal cancer to interferon-?. Cancer Immunol Immunother. 2013; 62: 517-27.

Tania M, Khan MA, Fu J. Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumor Biol. 2014; 35: 7335-42.

To K, Fotovati A, Reipas KM, Law JH, Hu K, Wang J, Astanehe A, Davies AH, Lee L, Stratford AL, Raouf A. Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance. Cancer Res. 2010; 70: 2840-51.

Tsofack SP, Garand C, Sereduk C, Chow D, Aziz M, Guay D, Yin HH, Lebel M. NONO and RALY proteins are required for YB-1 oxaliplatin induced resistance in colon adenocarcinoma cell lines. Molecular Cancer. 2011; 10: 145.

Uchiumi T, Fotovati A, Sasaguri T, Shibahara K, Shimada T, Fukuda T, Nakamura T, Izumi H, Tsuzuki T, Kuwano M, Kohno K. YB-1 Is important for an early stage embryonic development neural tube formation and cell proliferation. J Biol Chem. 2006; 281: 40440-49.

Unkrüer B, Pekcec A, Fuest C, Wehmeyer A, Balda MS, Horn A, Baumgärtner W, Potschka H. Cellular localization of Y-box binding protein 1 in brain tissue of rats, macaques, and humans. BMC Neurosci. 2009; 10: 1.

van Roeyen CR, Scurt FG, Brandt S, Kuhl VA, Martinkus S, Djudjaj S, Raffetseder U, Royer HD, Stefanidis I, Dunn SE, Dooley S. Cold shock Y-box protein-1 proteolysis auto-regulates its transcriptional activities. Cell Commun Signal. 2013; 11: 1.

Wang H, Sun R, Gu M, Li S, Zhang B, Chi Z, Hao L. shRNA-Mediated Silencing of Y-Box Binding Protein-1 (YB-1) Suppresses Growth of Neuroblastoma Cell SH-SY5Y In vitro and In vivo. PloS one. 2015; 10: e0127224.

Wang Y, Chen Y, Geng H, Qi C, Liu Y, Yue D. Overexpression of YB1 and EZH2 are associated with cancer metastasis and poor prognosis in renal cell carcinomas. Tumor Biol. 2015; 36: 7159-66.

Wu J, Lee C, Yokom D, Jiang H, Cheang MC, Yorida E, Turbin D, Berquin IM, Mertens PR, Iftner T, Gilks CB. Disruption of the Y-box binding protein-1 results in suppression of the epidermal growth factor receptor and HER-2. Cancer Res. 2006; 66: 4872-79.

Wu J, Stratford AL, Astanehe A, Dunn SE. YB-1 is a transcription/translation factor that orchestrates the oncogenome by hardwiring signal transduction to gene expression. Transl Oncogenomics. 2007; 2: 49.

Wu Y, Wang KY, Li Z, Liu YP, Izumi H, Uramoto H, Nakayama Y, Ito KI, Kohno K. Y-box binding protein 1 enhances DNA topoisomerase 1 activity and sensitivity to camptothecin via direct interaction. J Exper Clin Cancer Res. 2014; 33: 1.

Wu Y, Wang KY, Li Z, Liu YP, Izumi H, Yamada S, Uramoto H, Nakayama Y, Ito K, Kohno K. Y-box binding protein 1 expression in gastric cancer subtypes and association with cancer neovasculature. Clin Transl Oncol. 2015; 17: 152-59.

Wu Y, Yamada S, Izumi H, Li Z, Shimajiri S, Wang KY, Liu YP, Kohno K, Sasaguri Y. Strong YB?1 expression is associated with liver metastasis progression and predicts shorter disease?free survival in advanced gastric cancer. J Surg Oncol. 2012; 105: 724-30.

Xu S, Wang T, Song W, Jiang T, Zhang F, Yin Y, Jiang SW, Wu K, Yu Z, Wang C, Chen K. The inhibitory effects of AR/miR-190a/YB-1 negative feedback loop on prostate cancer and underlying mechanism. Sci Rep. 2015; 5: 13528.

Yahata H, Kobayashi H, Kamura T, Amada S, Hirakawa T, Kohno K, Kuwano M, Nakano H. Increased nuclear localization of transcription factor YB-1 in acquired cisplatin-resistant ovarian cancer. J Cancer Res Clin Oncol. 2002; 128: 621-26.

Yan J, Liu XL, Xiao G, Li NL, Deng YN, Han LZ, Yin LC, Ling LJ, Liu LX. Prevalence and clinical relevance of T-helper cells, Th17 and Th1, in hepatitis B virus-related hepatocellular carcinoma. PloS one. 2014; 9: e96080.

Yan X, Yan L. High expression of Y-box-binding protein 1 is associated with local recurrence and predicts poor outcome in patients with colorectal cancer. Int J Clin Exp Pathol. 2014; 7: 8715.

Yan XB, Zhu QC, Chen HQ, Peng JY, Chao HL, Du HX, Wang ZG, Jin ZM. Knockdown of Y box binding protein1 inhibits the malignant progression of HT29 colorectal adenocarcinoma cells by reversing epithelial mesenchymal transition. Mol Med Rep. 2014; 10: 2720-28.

Yasen M, Kajino K, Kano S, Tobita H, Yamamoto J, Uchiumi T, Kon S, Maeda M, Obulhasim G, Arii S, Hino O. The up-regulation of Y-box binding proteins (DNA binding protein A and Y-box binding protein-1) as prognostic markers of hepatocellular carcinoma. Clin Cancer Res. 2005; 11: 7354-61.

Yeh YT, Ou?Yang F, Chen IF, Yang SF, Wang YY, Chuang HY, Su JH, Hou MF, Yuan SS. STAT3 ser727 phosphorylation and its association with negative estrogen receptor status in breast infiltrating ductal carcinoma. Int. J Cancer. 2006; 118: 2943-47.

Yu YL, Su KJ, Hsieh MJ, Wang SS, Wang PH, Weng WC, Yang SF. Impact of EZH2 polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic features. PloS one. 2014; 9: e93635.

Yu YN, Yip GW, Tan PH, Thike AA, Matsumoto K, Tsujimoto M, Bay BH. Y-box binding protein 1 is up-regulated in proliferative breast cancer and its inhibition deregulates the cell cycle. Int J Oncol. 2010; 37: 483-92.

Zatsepina O, Baly C, Chebrout M, Debey P. The step-wise assembly of a functional nucleolus in preimplantation mouse embryos involves the Cajal (coiled) body. Dev Bio. 2003; 253: 66-83.

Zhang H, Cheng S, Zhang M, Ma X, Zhang L, Wang Y, Rong R, Ma J, Xia S, Du M, Shi F. Prostaglandin E2 promotes hepatocellular carcinoma cell invasion through up-regulation of YB-1 protein expression. Int J Oncol. 2014; 44: 769-80.

Zhang X, Ding Z, Mo J, Sang B, Shi Q, Hu J, Xie S, Zhan W, Lu D, Yang M, Bian W. GOLPH3 promotes glioblastoma cell migration and invasion via the mTOR?YB1 pathway in vitro. Mol Carcin. 2015; 54: 1252-63.

Zhang YF, Homer C, Edwards SJ, Hananeia L, Lasham A, Royds J, Sheard P, Braithwaite AW. Nuclear localization of Y-box factor YB1 requires wild-type p53. Oncogene 2003; 22: 2782-94.

Zhao BX, Sun YB, Wang SQ, Duan L, Huo QL, Ren F, Li GF. Grape seed procyanidin reversal of p-glycoprotein associa-ted multi-drug resistance via down-regulation of NF-?B and MAPK/ERK mediated YB-1 activity in A2780/T cells. PloS one. 2013; 8: e71071.




How to Cite

Gunasekaran, V. P., K. Nishi, V. Ravikumar, and G. Mathan. “Nuclear Shuttling of Y Box Binding Protein-1, Its Clinical Relevance in Cancer and As a Therapeutic Target”. Bangladesh Journal of Pharmacology, vol. 11, no. 2, Apr. 2016, pp. 501-24, doi:10.3329/bjp.v11i2.26759.



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