The long noncoding RNA GAS8-AS1 suppresses hepatocarcinogenesis by epigenetically activating the tumor suppressor GAS8.
Long noncoding RNAs (lncRNAs) are vital players in cancers, including hepatocellular carcinoma (HCC). We previously identified an lncRNA, GAS8-AS1, that is located in intron 2 of GAS8 However, its involvement in HCC is still largely unknown. In this study, we report that both GAS8-AS1 and its host gene GAS8 act as HCC tumor suppressors. We found that expression of GAS8-AS1 or GAS8 is significantly decreased in HCC tissues and is associated with a poor prognosis among HCC patients. Interestingly, lncRNA GAS8-AS1 could promote GAS8 transcription. We detected a CpG island in the GAS8 promoter, but lncRNA GAS8-AS1 did not affect DNA methylation at this GAS8 promoter site. Moreover, we identified two GAS8-AS1-interacting proteins, mixed-lineage leukemia 1 (MLL1), a histone 3 Lys-4 (H3K4) methyltransferase, and its partner WD-40 repeat protein 5 (WDR5). RNA pulldown, ChIP, and RNA immunoprecipitation assays revealed that GAS8-AS1 is required for maintaining the GAS8 promoter in an open chromatin state by recruiting the MLL1/WDR5 complex and for enhancing RNA polymerase II activity and GAS8 transcription. Of note, GAS8-AS1-dependent GAS8 hyperactivation inhibited malignant transformation of hepatocytes. Our results provide important insights into how lncRNA GAS8-AS1 suppresses HCC development and suggest potential strategies for treating patients with liver cancer.
['Pan|Wenting|W|', 'Zhang|Nasha|N|', 'Liu|Wenjuan|W|', 'Liu|Jibing|J|', 'Zhou|Liqing|L|', 'Liu|Yang|Y|', 'Yang|Ming|M|']
D000818:Animals D063646:Carcinogenesis D006528:Carcinoma, Hepatocellular D045744:Cell Line, Tumor D002471:Cell Transformation, Neoplastic D018899:CpG Islands D003598:Cytoskeletal Proteins D019175:DNA Methylation D044127:Epigenesis, Genetic D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008113:Liver Neoplasms D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009363:Neoplasm Proteins D011401:Promoter Regions, Genetic D062085:RNA, Long Noncoding
GAS8-AS1 epigenetics GAS8 hepatocellular carcinoma MLL1 WDR5 apoptosis histone modification long noncoding RNA (long ncRNA, lncRNA) tumor suppressor gene