4.8 Article

Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis

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ONCOGENE
卷 41, 期 30, 页码 3778-3790

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SPRINGERNATURE
DOI: 10.1038/s41388-022-02394-8

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  1. Department of Veterans Affair (Biomedical Laboratory Research Development Service) [I01 BX000131]
  2. NIH [5 RO1 CA243247, RO1 CA211095]

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This article investigates the inactivation mechanism of retinoblastoma protein (RB1) in hepatocellular carcinoma (HCC). The study finds that overexpressed FOXM1 plays a critical role in HCC by binding to RB1 and DNMT3B to repress the expression of FOXO1, leading to the decrease in CDK-inhibitors and subsequent phosphorylation and inactivation of RB1. Inhibition of FOXM1 results in increased expression of FOXO1, activation of RB1, and senescence of HCC cells.
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The retinoblastoma protein (RB1), a regulator of cell proliferation, is functionally inactivated in HCC by CYCLIN D/E-mediated phosphorylation. However, the mechanism of RB1-inactivation is unclear because only small percentages of HCCs exhibit amplification of CYCLIN D/E or mutations in the CDK-inhibitory genes. We show that FOXM1, which is overexpressed and critical for HCC, plays essential roles in inactivating RB1 and suppressing RB1-induced senescence of the HCC cells. Mechanistically, FOXM1 binds RB1 and DNMT3B to repress the expression of FOXO1, leading to a decrease in the levels of the CDK-inhibitors, creating an environment for phosphorylation and inactivation of RB1. Consistent with that, inhibition of FOXM1 causes increased expression of FOXO1 with consequent activation of RB1, leading to senescence of the HCC cells, in vitro and in vivo. Also, repression-deficient mutants of FOXM1 induce senescence that is blocked by depletion of RB1 or FOXO1. We provide evidence that human HCCs rely upon this FOXM1-FOXO1 axis for phosphorylation and inactivation of RB1. The observations demonstrate the existence of a new autoregulatory loop of RB1-inactivation in HCC involving a FOXM1-FOXO1 axis that is required for phosphorylation of RB1 and for aggressive progression of HCC.

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