WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1

• Published in: Molecular cancer Vol. 18; no. 1; pp. 127 - 19
• Main Authors: Chen, Yunhao, Peng, Chuanhui, Chen, Junru, Chen, Diyu, Yang, Beng, He, Bin, Hu, Wendi, Zhang, Yanpeng, Liu, Hua, Dai, Longfei, Xie, Haiyang, Zhou, Lin, Wu, Jian, Zheng, Shusen
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.08.2019; BioMed Central; BMC
• Subjects: Animals; Antigens; Cancer; Cancer genetics; Cancer therapies; Carcinogenesis; Carcinoma; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Care and treatment; Cell cycle; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell proliferation; Cell Transformation, Neoplastic; Chromatin; Cyclin-dependent kinase inhibitor p21; Development and progression; Disease Models, Animal; DNA Methylation; DNA microarrays; ELAV-Like Protein 1 - metabolism; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Ets-1 protein; ETS1; Female; Gene expression; Gene Silencing; Genes; Genetic aspects; Genomes; Genomics; Hepatocellular carcinoma; Hepatocellular carcinoma (HCC); Humans; HuR protein; Immunoprecipitation; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Luciferase; Male; Medical prognosis; Metastasis; Methylation; Methyltransferases; Methyltransferases - metabolism; Mice; Models, Biological; N6-methyladenosine; N6-methyladenosine (m6A); Neoplasm Staging; Nephroblastoma; Novels; Patient outcomes; Phenotypes; Post-transcription; Prognosis; Proteins; Proto-Oncogene Protein c-ets-1 - genetics; Ribonucleic acid; RNA; RNA sequencing; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; Survival analysis; Therapeutic applications; Tumor Burden; Tumorigenesis; Tumors; Wilms tumor 1-associated protein (WTAP); Writers; WT1 protein; Xenograft Model Antitumor Assays; Xenografts; N6-methyladenosine (m6A); Wilms tumor 1-associated protein (WTAP); ETS1; Hepatocellular carcinoma (HCC)
• DOI: 10.1186/s12943-019-1053-8
• ISSN: 1476-4598

N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer. We determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay. We demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1. We have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.