MiR-26a-1 Promotes DNA Damage Repair by Inhibiting Sirt1 and KDM5A in Human Liver Cancer Stem Cells

Abstract

Background: Although miR-26a-1 was down-regulated expressin in several cancers, the role of miR-26a-1in malignancies has yet to be systematically elucidated. Methods: RT-PCR, Western blotting and tumorigenesis test in vitro and in vivo were performed to analyze the signaling pathway. Results: miR-26a-1 inhibits the NAD(+)-dependent deacetylase Sirt1 expression by targeting the 3' non-coding region of Sirt1 which enhances the acetylation modification of H4 on the 16th lysine of histone and the expression of protein arginine methyltransferase PRMT6. Therefore, miR-26a-1 promotes arginine methylation modification of POLB (R137) and histone. On the other hand, miR-26a-1 inhibits the expression of KDM5A by targeting its 3' non-coding region, which enhances the methylation modification of histone H3 ysine 4. Moreover, miR-26a-1 enhances the expression of histone methyltransferase SETD2 dependent on H3K4me3 and further increases the trimethylation modification of the histone H3 lysine 36 . Significantly, miR-26a-1 promotes the formation of DNA damage repair complex (Rad51-PARP1-ATR-ATM-hMSH6-XRCC-POLB-SKP2) via H3K36me3. In particular, it was found that miR-26a-1 inhibited the function of long non-coding RNA HULC and promoted the formation of DNA damage repair complex. Furthermore, miR-26a-1 promotes the DNA damage repair ability by promoting the DNA damage repair complex to bind to the DNA damage site, thereby inhibiting the DNA damage of liver cancer stem cells. In particular, miR-26a-1 enhanced the binding of H3F3A to Skp2, CUL1, and F-box at the DNA damage site and enhanced the protein ubiquitination modification of H3F3A, which promoted Histone H3 replaces H3F3A by degrading H3F3A, realizing the renewal of histones after DNA damage repair. It was further found that miR-26a-1 inhibited the formation and instability of DNA microsatellites by promoting DNA damage repair, thereby affecting the expression of several cyclins and protein kinases in liver cancer stem cells, such as, inhibiting CDK2 and CyclinE , CDK4, CyclinD1, CDK6, CDK8, CyclinM2, CDK15, pRB, PCNA, MAP3K2, PGK1 and promoting RB, P18, P21/WAF1/Cip1, and thus inhibited the growth of liver cancer stem cells. Strikingly, the rescued-test further confirmed that excessive Sirt1 and KDM5A abrogated the oncogenic function of miR-26a-1. Conclusions: miR26a-1 may acts as the potential biomarker and therapeutic target for liver cancer.

Long Noncoding RNAs and Circular RNAs Regulate AKT and Its Effectors to Control Cell Functions of Cancer Cells

“…HULC induces autophagy of liver cancer cells [86]. HULC enhances the DNA repair of liver cancer stem cells [87]. Additionally, hepatitis B virus X protein upregulates HULC and downregulates senescence protein p18 expressions, suggesting that HULC can modulate cellular senescence [88].…”