Long noncoding RNA MEG3 blocks telomerase activity in human liver cancer stem cells epigenetically

Abstract Background: MEG3 is abnormally down-regulated in most tumors and inhibits tumorigenesis. Methods: Gene infection, Western blotting and tumorigenesis test in vitro and in vivo were performed to analyze the signaling pathway. Results: MEG3 increased the loading of P300 and RNA polymerase II onto the promoter regions of P53. Notably, MEG3 increased the methylation of histone H3 at lysine 27 through increasing the interplay between PRC2 and histone H3. Furthermore, MEG3 inhibited the expression of TERT by increasing the H3K27me3 and decreasing the loading of RNA pol Ⅱ in TERT promoter regions. Moreover, MEG3 inhibit the activity of telomerase by reducing the binding of TERT to TERC competitively. In addition, MEG3 also increased the TERRA through reducing DNA methyltransferase DNMT3b binding to the promoter regions of TERRA competitively. Therefore, the interaction between TERC and TERT was competitively attenuated by increasing the interaction between TERRA and TERT, which inhibited the activity of telomerase in hLCSCs.In particular, MEG3 shortened the length of telomere by blocking the formation of complex maintaining telomere length(POT1-Exo1-TRF2-SNM1B) and decreasing the binding of the complex to telomere competitively, which was caused by increasing the interplay between P53 and HULC in hLCSCs.Strikingly, MEG3 inhibited the growth in vitro and in vivo of hLCSCs by reducing the activity of telomerase and attenuating telomeric repeat binding factor 2(TRF2). Conclusions: our results demonstrated MEG3 inhibits the occurrence of human liver cancer and these findings provide an important insight into the prevention and treatment of human liver cancer.