Figure 9
The schematic diagram illustrates a model that The synergetic effect of HULC and MALAT1 promotes liver cancer growth through upregulation of TRF2.
Our results show that HULC, MALAT1 and TRF2 are highly expressed in hepatocellular carcinoma tissues, and present a positive correlation. Furthermore, HULC, MALAT1 overexpression promotes the growth of liver cancer stem cells in vitro and in vivo. Mechanistically, HULC, MALAT1 overexpression resulted in more RNApolII, P300, CREPT to load onto the promoter region of TRF2, enhancing the TRF2 expression at the level of transcription and its phosphorylation and SUMOylation. At the same time, the increased TRF2 binds to HULC, MALAT1 into complex that loads to the telomeric region of the chromosome, replacing the CST/AAF and the recruiting of POT1, pPOT1, ExoI, SNM1B, HP1 α. Accordingly, the telomere is greatly lengthened. On the other hand, the increased TRF2 reduced the methylation of the TERC promoter, increasing the TERC expression that results in a increase of interaction between TRET and TERC, Thus, activity of telomerase is raised. Ultimately, the microsatallite instability (MSI) is increased, and the interaction between RFC and PCNA or between CDK2 and CyclinE is increased in the liver cancer stem cells, which led to the rapid growth of liver cancer stem cells.
