Targeting Mybbp1a suppresses HCC progression via inhibiting IGF1/AKT pathway by CpG islands hypo-methylation dependent promotion of IGFBP5

BACKGROUND: Myb-binding protein 1A (Mybbp1a) is a nucleolar protein that can regulate rRNA metabolism, the stress response and carcinogenesis. However, the function of Mybbp1a in the progression of hepatocellular carcinoma (HCC) is unclear. We aimed to determine the role of Mybbp1a in HCC and the underlying mechanism. METHODS: We investigated the function of Mybbp1a in HCC cell models and the xenograft mouse model. The relationship between Mybbp1a and IGFBP5 was found through expression profile chip. The molecular mechanism of Mybbp1a regulating IGFBP5 was proved through CO-IP, CHIP, Bisulfite Sequencing and Pyrosequencing. FINDINGS: In this study, we observed that Mybbp1a was overexpressed in HCC tissues and associated with the poor prognosis of HCC patients. Suppression of Mybbp1a led to a reduction in the proliferation and migration ability of HCC cells through inhibiting the IGF1/AKT signaling pathway. Further study found that Mybbp1a could form a complex with DNMT1 and induce aberrant hyper-methylation of CpG islands of IGFBP5, which inhibits secretion of IGFBP5 and then activates IGF1/AKT signaling pathway. INTERPRETATION: These findings extend our understanding of the function of Mybbp1a in the progression of HCC. The newly identified Mybbp1a may provide a novel biomarker for developing potential therapeutic targets of HCC. FUND: Science Technology Department of Zhejiang Province (No. 2015C03034), National Health and Family Planning Commission of China (No. 2016138643), Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No. 91542205).