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VHL-Regulated MiR-204 Suppresses Tumor Growth through Inhibition of LC3B-Mediated Autophagy in Renal Clear Cell Carcinoma

2012; Cell Press; Volume: 21; Issue: 4 Linguagem: Inglês

10.1016/j.ccr.2012.02.019

1878-3686

Olga Mikhaylova, Yiwen Stratton, Daniel Hall, Emily Kellner, Birgit Ehmer, Angela F. Drew, Catherine A. Gallo, David R. Plas, Jacek Biesiada, Jarek Meller, Maria Czyzyk-Krzeska,

Epigenetics and DNA Methylation

Summary The von Hippel-Lindau tumor-suppressor gene ( VHL ) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Of note, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF-regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor-suppressing regulator of autophagic programs.