Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma

CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC. Mechanistic investigations revealed that inhibition of CIP2A significantly attenuated cellular proliferation in vitro and tumourigenicity in vivo. Bioinformatic analysis suggested that CIP2A might be involved in regulating cell cycle. Our experimental data further confirmed CIP2A knockdown induced cell cycle arrest at G1 phase. We found accumulated cellular senescence in HCC cells with CIP2A knockdown, companying expression changes of senescence associated proteins (p21, CDK2, CDK4, cyclin D1, MCM7 and FoxM1). Mechanistically, CIP2A knockdown repressed FoxM1 expression and induced FoxM1 dephosphorylation. Moreover, inhibition of PP2A by phosphatase inhibitor rescued the repression of FoxM1. Taken together, our results showed that CIP2A was highly expressed in HCC. Inhibition of CIP2A induced cell cycle arrest and promoted cellular senescence via repressing FoxM1 transcriptional activity, suggesting a potential anti-cancer target for patients with HCC.