MEX3A mediates DHRS3 instability to relieve G0/G1 arrest and facilitate hepatocellular carcinoma tumorigenesis and progression.

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, has a high incidence and mortality rate. This study aimed to elucidate the function of MEX3A in HCC and explore its underlying mechanisms. The expression of MEX3A was assessed in a DEN/CCl4-induced mouse model and in clinical HCC tumor tissues. MEX3A expression was increased in the tumors of HCC patients and was associated with poor prognosis. CRISPR/Cas9-mediated MEX3A knockout induced cell cycle arrest at the G0/G1 phase and suppressed the proliferation of HCC cells. Knockout of Mex3a hampered tumor development in DEN/CCl4-induced mice and inhibited xenograft tumor growth. MEX3A reduces the mRNA stability of DHRS3 via MRE. Knockdown of DHRS3 compromised the effect of MEX3A knockout on the HCC cell cycle and promoted HCC development. MEX3A transcription in HCC was regulated by ZKSCAN5. Knockout of ZKSCAN5 induced HCC cell cycle arrest at the G0/G1 phase and suppressed HCC cell proliferation. Sincalide, a compound targeting ZKSCAN5, inhibited the malignant behavior of HCC cells. The findings of this study indicate that sincalide serves as a potential ZKSCAN5-targeting candidate compound. By binding to ZKSCAN5 and promoting its proteasome-dependent degradation, it offers a new avenue for regulating the ZKSCAN5/MEX3A/DHRS3 axis.