Constitutive beta-Catenin Overexpression Represses Lncrna MIR100HG Transcription via HDAC6-Mediated Histone Modification in Colorectal Cancer

Wnt/beta-catenin signaling plays a critical role in colonic carcinogenesis. However, non-coding RNAs (ncRNA) transcription-ally regulated by beta-catenin are largely unknown. Herein, we found that lncRNA MIR100HG (lnc-MIR100HG) negatively correlated with target genes of beta-catenin from The Cancer Genome Atlas colorectal carcinoma database, which was verified in 48 paired colorectal carcinoma specimens. In addition, constitutive overexpression of beta-catenin decreased primary and mature lnc-MIR100HG levels, whereas blockage of beta-catenin activity with siRNA or inhibitors significantly increased their expression. DNA pull-down and chromatin immunoprecipitation revealed the binding of beta-catenin/TCF4 to the MIR100HG promoter. Moreover, beta-catenin-forced expression reduced the enrichment of H3K27Ac, an active transcription marker, on the promoter, whereas beta-catenin inhibition reversed this effect. Furthermore, HDAC6 was recruited to the MIR100HG promoter and downregulated H3K27Ac enrichment in a beta-catenin-dependent manner. Besides, HDAC6 was upregulated and negatively correlated with lnc-MIR100HG in colorectal carcinoma specimens. Functional studies showed that lnc-MIR100HG overexpression induced cell-cycle G(0)-G(1) arrest and repressed cell proliferation via p57 upregulation in vitro and in vivo. Taken together, we found that ectopic beta-catenin transcriptionally repressed lnc-MIR100HG expression through HDAC6-mediated histone modification in colorectal carcinoma. Lnc-MIR100HG regulates the cell cycle through p57. Implications: It provides a novel downstream mechanism highlighting beta-catenin action during colon carcinogenesis and may shed light for further therapeutic approaches.