Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis.
Hepatocellular carcinoma evades RB1-induced senescence by activating the FOXM1-FOXO1 axis.
复制标题
肝细胞癌通过激活FOXM1-FOXO1轴避免RB1诱导的衰老。
DOI：
10.1038/s41388-022-02394-8
复制
发表时间：
2022-07
期刊：
影响因子：
8
通讯作者：
Raychaudhuri, Pradip
中科院分区：
文献类型：
--
作者：
Chand, Vaibhav;Liao, Xiubei;Guzman, Grace;Benevolenskaya, Elizaveta;Raychaudhuri, Pradip
肝细胞癌（HCC）是最致命的癌症之一。视网膜母细胞瘤蛋白（RB 1）是一种细胞增殖调节因子，在肝癌中通过细胞周期蛋白D/E介导的磷酸化而功能性失活。然而，RB 1失活的机制尚不清楚，因为只有小部分HCC表现出细胞周期蛋白D/E的扩增或CDK抑制基因的突变。我们发现，FOXM 1，这是过表达的HCC的关键，在灭活RB 1和抑制RB 1诱导的HCC细胞衰老中起着至关重要的作用。从机制上讲，FOXM 1结合RB 1和DNMT 3B以抑制FOXO 1的表达，导致CDK抑制剂水平降低，为RB 1的磷酸化和失活创造环境。与此一致，FOXM 1的抑制导致FOXO 1表达增加，随后RB 1活化，导致HCC细胞在体外和体内衰老。此外，FOXM 1的阻遏缺陷突变体诱导衰老，其通过RB 1或FOXO 1的耗尽而被阻断。我们提供的证据表明，人类肝癌依赖于这个FOXM 1-FOXO 1轴的磷酸化和RB 1的失活。这些观察结果表明，在HCC中存在一个新的RB 1失活的自动调节环，涉及RB 1磷酸化和HCC侵袭性进展所需的FOXM 1-FOXO 1轴。
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 expression of FOXO1, leading to 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 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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DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
21.3
作者：
Laoukili, J;Kooistra, MRH;Medema, RH
通讯作者：
Medema, RH
影响因子：
4.3
作者：
Diep, Caroline H.;Charles, Nathan J.;Lange, Carol A.
通讯作者：
Lange, Carol A.
影响因子：
64.8
作者：
通讯作者：
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