Inhibition of Annexin A10 Contributes to ZNF281 Mediated Aggressiveness of Hepatocellular Carcinoma

Abstract

Xialu Zhang,1,* Chenguang Zhang,1,2,* Qingfang Zhao,1 Shanshan Wang,3 Liyong Wang,4 Yang Si,1 Qiang Su,5 Shan Cheng,1 Wei Ding1 1School of Basic Medical Sciences, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory for Cancer Invasion and Metastasis Mechanism Research, Capital Medical University, Beijing, People’s Republic of China; 3Beijing Institute of Hepatology, Beijing You’An Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Core Facilities for Molecular Biology, Capital Medical University, Beijing, People’s Republic of China; 5Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chenguang Zhang; Wei Ding, Email [email protected]; [email protected]: 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.Graphical Abstract: Keywords: zinc finger protein 281, Annexin A10, nucleosome remodeling and deacetylation complex, hepatocellular carcinoma, invasion and metastasis, transcription

Keywords

• zinc finger protein 281
• annexin a10
• nucleosome remodeling and deacetylation complex
• hepatocellular carcinoma
• invasion and metastasis
• transcription.