膜联蛋白A10的抑制作用有助于锌指蛋白281介导的肝细胞癌侵袭性。
Inhibition of Annexin A10 Contributes to ZNF281 Mediated Aggressiveness of Hepatocellular Carcinoma.
作者信息
Zhang Xialu, Zhang Chenguang, Zhao Qingfang, Wang Shanshan, Wang Liyong, Si Yang, Su Qiang, Cheng Shan, Ding Wei
机构信息
School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China.
Beijing Key Laboratory for Cancer Invasion and Metastasis Mechanism Research, Capital Medical University, Beijing, People's Republic of China.
出版信息
J Hepatocell Carcinoma. 2023 Apr 5;10:553-571. doi: 10.2147/JHC.S400989. eCollection 2023.
OBJECTIVE
To investigate the involvement and transcriptional targets of zinc finger protein 281 (ZNF281) in the progression of hepatocellular carcinoma (HCC).
METHODS
The expression of ZNF281 in HCC was detected in tissue microarray and cell lines. The role of ZNF281 in aggressiveness of HCC was examined using wound healing, matrigel transwell, pulmonary metastasis model and assays for expression of EMT markers. RNA-seq was used to find potential target gene of ZNF281. Chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (Co-IP) were employed to uncover the mechanism of the transcriptional regulation of ZNF281 on the target gene.
RESULTS
ZNF281 was increased in tumor tissues and positively correlated with vascular invasion in HCC. Knockdown of ZNF281 suppressed the migration and invasion with significant alteration of EMT marker expression in HLE and Huh7 HCC cell lines. RNA-seq screening showed that the tumor suppressor gene Annexin A10 (ANXA10) was a most up-regulated gene in response to ZNF281 depletion and responsible for the attenuation of aggressiveness. Mechanistically, ZNF281 interacted with the ANXA10 promoter region harboring ZNF281 recognition sites, and recruited components of nucleosome remodeling and deacetylation (NuRD) complex. By knocking down such components like HDAC1 or MTA1, ANXA10 was released from transcriptional repression by ZNF281/NuRD, and in turn reversed the EMT, invasion and metastasis driven by ZNF281.
CONCLUSION
ZNF281 drives invasion and metastasis of HCC partially through transcriptional repression of tumor suppressor gene ANXA10 by recruiting NuRD complex.
目的
研究锌指蛋白281（ZNF281）在肝细胞癌（HCC）进展中的作用及转录靶点。
方法
在组织芯片和细胞系中检测ZNF281在HCC中的表达。采用伤口愈合实验、基质胶Transwell实验、肺转移模型以及上皮-间质转化（EMT）标志物表达检测，研究ZNF281在HCC侵袭性中的作用。利用RNA测序（RNA-seq）寻找ZNF281的潜在靶基因。采用染色质免疫沉淀（ChIP）实验和免疫共沉淀（Co-IP）实验，揭示ZNF281对靶基因转录调控的机制。
结果
ZNF281在肿瘤组织中表达升高，且与HCC中的血管侵犯呈正相关。敲低ZNF281可抑制HLE和Huh7 HCC细胞系的迁移和侵袭，并显著改变EMT标志物的表达。RNA-seq筛选显示，肿瘤抑制基因膜联蛋白A10（ANXA10）是ZNF281缺失时上调最明显的基因，且与侵袭性减弱有关。机制上，ZNF281与含有ZNF281识别位点的ANXA10启动子区域相互作用，并募集核小体重塑去乙酰化（NuRD）复合体的成分。通过敲低HDAC1或MTA1等成分，ANXA10从ZNF281/NuRD的转录抑制中释放出来，进而逆转ZNF281驱动的EMT、侵袭和转移。
结论
ZNF281通过募集NuRD复合体对肿瘤抑制基因ANXA10进行转录抑制，从而部分驱动HCC的侵袭和转移。
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