lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying their self-renewal and differentiation remain largely unknown. Through analysis of transcriptome microarray data, we identified a long noncoding RNA (lncRNA) called lnc-beta-Catm, which is highly expressed in human HCC tumors and liver CSCs. We found that lnc-beta-Catm is required for self-renewal of liver CSCs and tumor propagation in mice. lnc-beta-Catm associates with beta-catenin and the methyltransferase EZH2, thereby promoting beta-catenin methylation. Methylation suppresses the ubiquitination of beta-catenin and promotes its stability, thus leading to activation of Wnt-beta-catenin signaling. Accordingly, the expression of lnc-beta-Catm, EZH2 and Wnt-beta-catenin targets is positively correlated with cancer severity and prognosis of people with HCC.