HIF-2a promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity (Cancer Cell, 2007, 11:335-347)

HIF-2a Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

Authors: John D. Gordan, Jessica A. Bertout, Cheng-Jun Hu, J. Alan Diehl, and M. Celeste Simon.

Journal: Cancer Cell 11, 335–347, 2007

Student: Chun-Chieh Lin

Commentator: Prof. Shaw-Jenq Tsai

Time: 16:00 – 17:00, 26 Oct, 2007.

Room 602

Abstract:

  Hypoxia induces tumor angiogenesis, invasion and metastasis. Hypoxia-response genes expression is majorly regulated by hypoxia-induced factors (HIFs). The HIF a subunits, HIF-1a and HIF-2a, both can form heterodimers with b subunit respectively to regulate downstream genes expression by binding hypoxia response elements (HREs). Previous studies show that HIF-1a induces cell-cycle arrest by antagonizing c-Myc binding function with Sp1, Miz1 and Max transcription factors. HIF-2a promotes VHL-null renal cell carcinoma (RCC) but the mechanism is not clear, whereas HIF-1a inhibits the growth of RCC. The authors hypothesized that HIF-2a promotes cell-cycle progression by enhancing c-Myc functions under hypoxia. Western blot and BrdU analysis showed that overexpression of HIF-2a not only promoted cell-cycle progression not only in RCC cells but in NIH3T3 cells and mouse primary embryo fibroblasts. Increased expression level of HIF-2a improved c-Myc binding activity to its target gene promoters by ChIP assay, and HIF-2a stablized c-Myc in forming complexes with Sp1, Miz1, and Max, respectively. QRT-PCR results showed c-Myc could upregulate target genes which promote cell-cycle progression. Taken together, the authors suggest that HIF-2a enhances c-Myc functions to promote cell-cycle progression.

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