CircHULC accelerates the growth of human liver cancer stem cells by enhancing chromatin reprogramming and chromosomal instability via autophagy

Abstract

Background: Although CircHULC was overexpressed in several cancers, the role of CircHULC in malignancies has yet to be elucidated.

Methods: Gene infection, tumorigenesis test in vitro and in vivo and the signaling pathway analysis were performed.

Results: our results indicate that CircHULC promotes growth of human liver cancer stem cells and the malignant differentiation of hepatocyte-like cells. Mechanistically, CircHULC enhances the methylation modification of PKM2 via CARM1 and the deacetylase Sirt1. Moreover, CircHULC enhances the binding ability of TP53INP2/DOR with LC3 and LC3 with ATG4, ATG3, ATG5, ATG12. Therefore, CircHULC promotes the formation of autophagosomes. In particular, the binding ability of phosphorylated Beclin1 (Ser14) to Vps15, Vps34, ATG14L were significantly increased after CircHULC was overexpressed. Strikingly, CircHULC affects the expression of chromatin reprogramming factors and oncogenes through autophagy. Thereafter, Oct4, Sox2, KLF4, Nanog, and GADD45 were significantly decreased and C-myc was increased after CircHULC was overexpressed. Thus, CircHULC promotes the expression of H-Ras, SGK, P70S6K, 4E-BP1, Jun, and AKT. Interestingly, both CARM1 and Sirt1 determine the cancerous function of CircHULC dependent on autophagy.

Conclusions: we shed light on the fact that the targeted attenuation of deregulated functioning of CircHULC could be a viable approach for cancer treatment, and CircHULC may acts as the potential biomarker and therapeutic target for liver cancer.

Keywords: Autophagy; CARM1; CircHULC; Human liver cancer stem cells; PKM2; Sirt1.