UPF3B Accelerates the Growth of Liver Cancer Cells by Enhancing Autophagy via CDK12.

Abstract

UPF3B encodes a protein that is part of a postsplicing multi-protein complex involved in both mRNA nuclear export and mRNA surveillance. Herein, we demonstrate that UPF3B accelerates the proliferation ability of liver cancer cells in vitro and in vivo. Moreover, UPF3B affects epigenetic regulation in human liver cancer cells. Moreover, ATAC-seq results show that chromatin accessibility is changed between rLV group and rLV-UPF3B group. Therefore, UPF3B alters transcriptome and proteome in liver cancer. In particular, UPF3B affects the heterogeneity of liver cancer and its microenvironment network. Furthermore, UPF3B promotes the modification ability of H3K4me3, H4K16Ac, and RNAPolII on promoter region of CDK12 and then increased the expression of CDK12. Strikingly, UPF3B enhances the interaction between LC3 and DOR, ATG4 and LC3, ATG3 and LC3, ATG3 and ATG12, ATG3 and ATG16L1, ATG3 and ATG7, ATG3 and ATG9A, and the expression of activated LC3, beclin1 dependent on CDK12. Ultimately, UPF3B increases the autophagy via CDK12 and then enhances the expression of ARAF, RRAS, CyclinD1, C-myc, PCNA, PKM2, CDK4, YB-1, H-Ras via CDK12-autophagy pathway. Importantly, our results indicate that CDK12 determines the oncogenic function of UPF3B. In conclusions, these results provide basis for research on liver cancer prevention and treatment.