Abstract
microRNAs (miRNAs) are short non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miR675, embedded in H19's first exon, had been linked to the development of human cancers. Herein, we demonstrate miR675 overexpression promotes and silencing miR675 attenuated liver cancer cell growth in vitro and in vivo. Mechanistically, miR675 inhibits the heterochromatin1 isoform HP1α expression in human liver cancer cells which causes a dramatically decrease of the total histone H3 lysine 9 trimethylation (H3K9me3) , histone H3 lysine 27 trimethylation (H3K27me3) and a increase of histone H3 lysine 27 acetylation(H3K27Ac).Notably, a significant reduction of the H3K9me3 and H3K27me3 and the increment of H3K27Ac occupancy on the promoter region of EGR1 triggers EGR1 transcription, translation, sumoylation and activation which upregulates lincRNA H19. Strikingly, H19 may induce and activate tumor-specific pyruvate kinase M2 (PKM2) which is essential for the Warburg effect in its dimer and for gene expression in its teramer during tumorigenesis. Our results imply that miR675 is involved in the epigenetic regulation of H3K9me3, H3k27me3 and H3K27Ac for gene expression and function during hepatocarcinogenesis (e.g.C-myc,Pim1,Ras,CyclinD1,RB1).These findings sheds light on the significance of miR675-HP1α-EGR1-H19-PKM2 cascade signaling pathway in liver cancer.
Highlights
Primary liver cancer are an increasing global health problem, with hepatocellular carcinoma (HCC) being the third leading cause of cancer-related mortality worldwide [1]
This is the first report demonstrating miR675 plays a positive role in liver carcinogenesis through the cascade of miR675-HP1α-early growth response protein1 (EGR1)-H19-pyruvate kinase M2 (PKM2) signaling
We report that the upregulated expression level of miR675, H19, HP1α, EGR1, PKM2, H-Ras were consistent in liver cancer patients and miR-675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer cells
Summary
Primary liver cancer are an increasing global health problem, with hepatocellular carcinoma (HCC) being the third leading cause of cancer-related mortality worldwide [1]. Overexpression of miR-675 in a range of embryonic and extra-embryonic cell lines results in their reduced proliferation [2]. H19 regulates glioma development by deriving miR-675 which modulated Cadherin 13 expression by directly targeting the binding site within the 3’ UTR [5].In addition, H19 maintain hematopoietic stem cell repopulating ability through a miR-675-IGFR signaling circuit [6]. MiR675 was significantly downregulated in the metastatic prostate cancer cell and directly bound with 3’UTR of transforming growth factor β induced protein (TGFBI, an extracellular matrix protein involved in cancer metastasis) mRNA to repress its translation [7]. H19 gene could www.impactjournals.com/oncotarget inhibit human trophoblast cell proliferation via encoding miR675 that targeted NOMO1 and interferes with Nodal signaling [8]. The exact roles of mature miR-675 in hepatocarcinogenesis have not been identified
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