Trichostatin A destabilizes HIF-2α through a VHL-independent but proteasome-dependent pathway in cancer cell lines and tumor xenografts

  • Qingcheng Yang Department of Orthopedics, Sixth People's Hospital, Shanghai JiaoTong University, Shanghai 200233
  • Yuzhen Du Department of Clinical Laboratory, Sixth People’s Hospital, Shanghai JiaoTong University, Shanghai 200233
  • Dongdong Cheng Department of Orthopedics, Sixth People's Hospital, Shanghai JiaoTong University, Shanghai 200233
  • Zhichang Zhang Department of Orthopedics, Sixth People's Hospital, Shanghai JiaoTong University, Shanghai 200233
  • Xinhui Du Department of Orthopedics, Sixth People's Hospital, Shanghai JiaoTong University, Shanghai 200233
Keywords: Cancer cell line, HIF-2α, Proteasome, Trichostatin A, Tumor xenograft, VHL

Abstract

Histone deacetylase (HDACs) inhibitors are a new generation of anti-cancer agents. Little is known regarding the effect of HDAC inhibitors on HIF-2α. The effect of trichostatin A (TSA), a class I/II HDAC inhibitor, on HIF-2α protein expression was investiagted in cancer cell lines and tumor xenografts. Results showed TSA inhibited the HIF-2α protein expression in a dose-dependent manner, which was VHL-independent, but proteasome-dependent in cell lines. In tumor xenografts, TSA inhibited tumor growth and HIF-2α expression. Knocking down of HDAC6 by small RNA interfering decreased HIF-2α protein expression. HDAC6 physically interracted with HIF-2α, and HIF-2α was acetylated by TSA. TSA destabilizes HIF-2α in a proteasome dependent manner, which is unrelated to VHL, suggesting the anticancer effect of TSA is at least partially mediated by its inhibition of HIF-2α, which provides a new insight into the molecular mechanism underlying the anticancer effect of HDAC inhibitors.

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Published
2013-03-24
How to Cite
Yang, Q., Y. Du, D. Cheng, Z. Zhang, and X. Du. “Trichostatin A Destabilizes HIF-2α through a VHL-Independent But Proteasome-Dependent Pathway in Cancer Cell Lines and Tumor Xenografts”. Bangladesh Journal of Pharmacology, Vol. 8, no. 2, Mar. 2013, pp. 142-8, doi:10.3329/bjp.v8i2.13842.
Section
Research Articles