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

Abstract

Abstract Background MEG3 downregulated the expression in several tumors and inhibits human tumorigenesis. But so far, the mechanism of MEG3 in tumorigenesis is still unclear. Methods In gene infection, cellular and molecular technologies and tumorigenesis test in vitro and in vivo were performed, respectively. Results Our results indicate that MEG3 enhances the P53 expression by triggering the loading of P300 and RNA polymerase II onto its promoter regions dependent on HP1α. Moreover, MEG3 increases the methylation modification of histone H3 at the 27th lysine via P53. Furthermore, MEG3 inhibits the expression of TERT by increasing the H3K27me3 in TERT promoter regions, thereby inhibiting the activity of telomerase by reducing the binding of TERT to TERC. Furthermore, MEG3 also increases the expression of TERRA; therefore, the interaction between TERC and TERT was competitively attenuated by increasing the interaction between TERRA and TERT, which inhibits the activity of telomerase in hLCSCs. Strikingly, MEG3 reduces 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 by increasing the interplay between P53 and HULC. Ultimately, MEG3 inhibits the growth of hLCSCs by reducing the activity of telomerase and attenuating telomeric repeat binding factor 2(TRF2). Conclusions Our results demonstrates MEG3 inhibits the occurrence of human liver cancer by blocking telomere, and these findings provide an important insight into the prevention and treatment of human liver cancer.

Keywords

• Liver cancer stem cell
• MEG3
• P53
• HP1α
• HULC
• TERT