Knockdown of linc01320 for RNA-seq sequencing
Clear cell renal cell carcinoma (ccRCC) is a highly prevalent malignancy of the urinary system and a major cause of renal cancer-related mortality. ccRCC pathogenesis has been observed to be associated with hypoxia-inducible factor 2Alpha (HIF2-Alpha), a master transcriptional regulator, which promotes tumor progression via different oncogenic pathways. This study aimed to identify whether HIF2-Alpha acts as a transcriptional activator of the long non-coding RNA LINC01320, which is specifically and significantly overexpressed in ccRCC tissues. Subcellular fractionation and RNA pull-down mass spectrometry analyses validated that LINC01320 had a nuclear localization and directly interacted with acetyl-CoA carboxylase 1 (ACC1). Similarly, immunoprecipitation-mass spectrometry showed that LINC01320 serves as a scaffold to recruit USP10 to ACC1, thus protecting ACC1 ubiquitin-mediated degradation. Moreover, ACC1-mediated metabolic coupling of acetyl-CoA and malonyl-CoA promoted epigenetic regulation by dynamic modulation of histone acetylation. CUT&amp;Tag analysis indicated that LINC01320-dependent ACC1 stabilization preferentially enhances histone H3 lysine 18 acetylation (H3K18ac) at the tumor necrosis factor alpha-induced protein 3 (TNFAIP3) promoter, which promotes its transcriptional activation. In conclusion, this study highlighted a novel axis wherein HIF2-Alpha-LINC01320-ACC1 promotes ccRCC apoptosis via histone acylation-mediated epigenetic reprogramming. As a ccRCC-specific lncRNA, LINC01320 acts as a molecular nexus associating metabolic adaptation to chromatin remodeling, thus providing new therapeutic strategies for ccRCC treatment.