LncRNA GAS8‐AS1 directs epigenetic modulation and activation of the tumor suppressor GAS8 via MLL1/WDR5 to suppress hepatocarcinogenesis

Abstract

Long noncoding RNAs (lncRNAs) are vital players in hepatocellular carcinoma (HCC). We previously identified a significantly mutated lncRNA GAS8‐AS1 locating in intron 2 of GAS8. However, its involvement in HCC is still largely unknown. In this study, we thoroughly functional evaluated its critical role in regulating chromatin dynamics, gene expression, cancer development and sorafenib multi‐kinase target therapy in HCC. We for the first time declare that GAS8‐AS1 and its host gene GAS8 act as novel HCC tumor suppressors employing a series of in vitro and in vivo assays. Consistent with this notion, a significantly decreased GAS8‐AS1 or GAS8 expression exists in HCC tissues and is associated with poor prognosis of HCC patients. Interestingly, lncRNA GAS8‐AS1 could evidently promote GAS8 transcription. Although GAS8‐ AS1 does not impact promoter DNA methylation of GAS8, we successfully annotated two lncRNA interacting proteins, Mixed Lineage Leukemia 1 (MLL1), a histone 3 Lys4 (H3K4) methyltransferase, and its partner WD‐40 Repeat Protein 5 (WDR5) based on bioinformatics methodology. Chromatin immunoprecipitation and RNA immunoprecipitation assays elucidate that lncRNA GAS8‐AS1 is required to maintain the GAS8 promoter in an open chromatin state. In accord with this, knockdown of GAS8‐AS1 results in reduced MLL1/WDR5 binding, decreased H3K4me3 levels, diminished RNA Pol II functions and gene silencing of GAS8. GAS8‐AS1 may function as part of a surveillance mechanism that keep activation of GAS8 promoter and transcription, which thus prevents hepatocarcinogenesis. Our results highlight the prevalent involvement of regulatory lncRNAs in cancers and provide pathogenic insights into HCC development and treatment.Support or Funding InformationNational Natural Science Foundation of China (31671300); Taishan Scholars Program of Shandong Province (tsqn20161060)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.