State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Cell Death Dis. 2024 Jan 15;15(1):55. doi: 10.1038/s41419-024-06441-y.
Hepatocarcinogenesis is a multi-step process. However, the regulators of hepatocellular carcinoma (HCC) initiation are understudied. Adult liver-specific gene expression was globally downregulated in HCC. We hypothesize that adult liver-specific genes, especially adult liver-enriched transcription factors may exert tumor-suppressive functions in HCC. In this study, we identify ZBTB7B, an adult liver-enriched transcription factor as a permissive regulator of HCC initiation. ZBTB7B is highly expressed in hepatocytes in adult livers, compared to fetal livers. To evaluate the functions of ZBTB7B in hepatocarcinogenesis, we performed hepatocyte-specific ZBTB7B knockout in hydrodynamic oncogene transfer-induced mouse liver cancer models. Hepatocyte-specific knockout of ZBTB7B promotes activated Akt and N-Ras-induced HCC development. Moreover, ZBTB7B deficiency sensitizes hepatocytes to a single oncogene Akt-induced oncogenic transformation and HCC initiation, which is otherwise incompetent in inducing HCC. ZBTB7B deficiency accelerates HCC initiation by down-regulating adult liver-specific gene expression and priming livers to a fetal-like state. The molecular mechanism underlying ZBTB7B functions in hepatocytes was investigated by integrated transcriptomic, phosphoproteomic, and chromatin immunoprecipitation-sequencing analyses. Integrative multi-omics analyses identify c-Jun as the core signaling node in ZBTB7B-deficient liver cancer initiation. c-Jun is a direct target of ZBTB7B essential to accelerated liver cancer initiation in ZBTB7B-deficient livers. Knockdown of c-Jun expression or dominant negative c-Jun expression delays HCC development in ZBTB7B-deficient livers. In addition, ZBTB7B competes with c-Jun for chromatin binding. Ectopic ZBTB7B expression attenuates the tumor-promoting functions of c-Jun. Expression of ZBTB7B signature, composed of 140 genes co-regulated by ZBTB7B and c-Jun, is significantly downregulated in early-stage HCCs compared to adjacent normal tissues, correlates to liver-specific gene expression, and is associated with good prognosis in human HCC. Thus, ZBTB7B functions as a permissive regulator of HCC initiation by directly regulating c-Jun expression and function.
肝癌发生是一个多步骤的过程。然而，肝细胞癌（HCC）起始的调控因子仍研究不足。HCC 中成年肝脏特异性基因表达被全局下调。我们假设成年肝脏特异性基因，特别是成年肝脏富集转录因子，可能在 HCC 中发挥肿瘤抑制作用。在这项研究中，我们确定 ZBTB7B，一种成年肝脏富集转录因子，是 HCC 起始的许可调节因子。与胎肝相比，成年肝脏中的肝细胞中 ZBTB7B 高表达。为了评估 ZBTB7B 在肝癌发生中的作用，我们在水力动力学癌基因转移诱导的小鼠肝癌模型中进行了肝细胞特异性 ZBTB7B 敲除。肝细胞特异性 ZBTB7B 敲除促进 Akt 和 N-Ras 激活诱导的 HCC 发展。此外，ZBTB7B 缺失使肝细胞对单个致癌基因 Akt 诱导的致癌转化和 HCC 起始敏感，否则在诱导 HCC 方面无能为力。ZBTB7B 缺失通过下调成年肝脏特异性基因表达并使肝脏向胎儿样状态启动，加速 HCC 起始。通过整合转录组、磷酸化蛋白质组和染色质免疫沉淀测序分析研究了 ZBTB7B 在肝细胞中的功能的分子机制。综合多组学分析确定 c-Jun 是 ZBTB7B 缺失性肝癌起始的核心信号节点。c-Jun 是 ZBTB7B 的直接靶标，对于 ZBTB7B 缺失性肝脏中的加速肝癌起始至关重要。c-Jun 表达的敲低或显性负性 c-Jun 表达延迟 ZBTB7B 缺失性肝脏中的 HCC 发展。此外，ZBTB7B 与 c-Jun 竞争染色质结合。异位 ZBTB7B 表达减弱了 c-Jun 的促肿瘤功能。由 ZBTB7B 和 c-Jun 共同调节的 140 个基因组成的 ZBTB7B 特征表达谱在早期 HCC 中与相邻正常组织相比显著下调，与肝脏特异性基因表达相关，并与人 HCC 的良好预后相关。因此，ZBTB7B 通过直接调节 c-Jun 的表达和功能，作为 HCC 起始的许可调节因子发挥作用。
