ZNF768 regulates expression of E2F1 protein to drive G0/G1 transition and cell cycle progression.

Abstract

Accurate and tightly coordinated cell cycle progression and cell proliferation are critical for development, growth and homeostasis of an organism. Recently, Zinc finger protein 768 (ZNF768) was identified as a transcription factor driving cellular proliferation, in both a p53-dependent and independent manner. ZNF768 interacts with and represses p53 functions to limit cell cycle delay. Independently, ZNF768 promotes the transcription of key regulators of the cell cycle machinery, although the mechanisms through which this occurs remain unknown. Here, we report that ZNF768 protein levels are tightly regulated during the cell cycle, and its depletion leads to cell cycle exit and induction of quiescence. We found that ZNF768 modulates the cell cycle, at least in part, by controlling expression of the major pro-proliferative transcription factor E2F1 independently of p53 activation. Consequently, depletion of ZNF768, which also represses expression of the key mitotic transcription factor and E2F1 target FOXM1, leads to numerous mitotic errors. Supporting these findings, cancer genomics analyses reveal that ZNF768 expression levels are positively associated with E2F1 and FOXM1 expression levels in human tumors, suggesting that cancer cells might use ZNF768 to override cell cycle arrest, sustain proliferation, and promote cancer progression. Altogether, our results reveal that ZNF768 modulates cell cycle entry and proliferation, at least in part by regulating E2F1 expression.