HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity (Cancer Cell, 2007, 11:407-420)

HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of c-MYC activity

Cancer Cell, 2007, 11: 407-420

Student: 賴泓霖

Time: 1510-1600, 10/26/07 

Commentator: 蔡少正 教授

Place: ROOM 602

Abstract:

    The characteristic feature of cancer cells is its increased metabolism of converting glucose to lactate even under aerobic condition. However, the molecular mechanism is unclear. Hypoxia-inducible factor (HIF)-1 is frequently up-regulated in many human cancers. The von Hippel-Lindau tumor suppressor (VHL) protein inhibits the function of HIF-1. It is known that VHL deficiency occurs in the early pathogenesis of renal cell carcinoma. Recent studies have shown that HIF-1 negatively regulates mitochondrial biogenesis and O₂ consumption in VHL-deficient renal carcinoma cells. C-MYC, a well-studied transcription factor, is known to promote mitochondrial biogenesis. This study aimed to identify a decreased energy metabolism, observed in renal cell carcinoma, is controlled by HIF-1 via C-MYC. Western blot analysis showed that HIF-1 inhibited C-MYC transcription through up-regulation of MXI-1 gene in VHL-deficient renal carcinoma RCC4 cells. In addition, HIF-1 promoted C-MYC degradation through a proteasome-dependent mechanism. Furthermore, authors demonstrated that PGC-1β functioned as a downstream mediator of C-MYC during mitochondrial biogenesis. In conclusion, HIF-1 regulates mitochondrial mass and respiration function by dominantly repressing the expression of C-MYC and PGC-1β. The findings suggest that the metabolic reprogramming induced by VHL deficiency via the HIF-1/C-MYC pathway may be a critical step during renal cell carcinogenesis.

Reference:

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2.          Papandreou, I., et al., HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab, 2006. 3: 187-197.