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Background: The functions of HULC have been demonstrated in several cancers. However, its mechanism has not been elucidated in human liver cancer stem cells. Methods: Liver cancer stem cells were isolated from Huh7 cells; gene infection and tumorigenesis test in vitro and in vivo were performed. Results: We demonstrate that HULC promotes growth of liver cancer stem cells in vitro and in vivo. Mechanistically, HULC enhances the expression of Sirt1 dependent on miR675 and then induces the cellular autophagy through Sirt1. HULC enhances CyclinD1 and thereby increases pRB and inhibited P21 WAF1/CIP 1 via autophagy-miR675-PKM2 pathway in human liver cancer stem cells. Ultimately, our results demonstrate that CyclinD1 is required for the oncogenic functions of HULC in liver cancer stem cells. Conclusions: It reveals the key molecular signaling pathways for HULC and provides important basic information for finding effective tumor therapeutic targets based on HULC. [ABSTRACT FROM AUTHOR]

Both miR675 and pyruvate kinase M2 (PKM2) contribute to malignant progression of tumor, but its functions in liver cancer stem cells remain unclear. Herein, our findings indicate that miR675 plus PKM2 strongly promotes the growth of liver cancer stem cells. Mechanistically, miR675 plus PKM2 enhances the transcriptional activity of SUV39h2. On the other hand, the excessive SUV39h2 binds to more substrate histone H3, triggering an increase of tri-methylation of histone H3 on the ninth lysine. Furthermore, the tri-methylation of histone 3 on the ninth lysine (H3K9me3)-heterochromatin protein 1 alpha (HP1α) complex is increased when the complex occupancy ability on the C-myc promoter region is raised, recruiting CREB, P300, and RNApolII to the special position that results in C-myc high abundance. Therefore, miR675 plus PKM2 triggered the upregulation of C-myc by increasing the interaction between H3K9me3 and HP1α. Understanding the signaling pathways that miR675 plus PKM2 epigenetically possesses during the malignant transformation of liver cancer stem cells will contribute to more effective liver cancer therapies. [ABSTRACT FROM AUTHOR]

Abstract: Toll‐like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone‐lysine N‐methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9‐heterochromatin protein 1‐telomere repeat binding factor 2 (H3K9me3‐HP1‐TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer‐associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat‐containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri‐complexes of HP1 isoforms (α, β and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]