PPP1R14B-mediated phosphorylation enhances protein stability of RPS6KA1 to promote hepatocellular carcinoma tumorigenesis

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide with a poor clinical prognosis. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B) is an unidentified protein phosphatase 1 regulatory subunit that is associated with the occurrence and development of various cancers. Recently, PPP1R14B was found to contribute to paclitaxel resistance and cell progression in triple-negative breast cancer; however, the role of PPP1R14B in HCC is unknown. Here, we found that PPP1R14B was highly expressed in HCC tissues, which suggested a poor prognosis. Knockdown of PPP1R14B significantly inhibited the survival and tumorigenic ability of HCC cells, while overexpression of PPP1R14B had the opposite effects. Mechanistically, Ribosomal Protein S6 Kinase type 1(RPS6KA1) was identified as the target gene of PPP1R14B. PPP1R14B maintained the stability and phosphorylation of RPS6KA1, and positively regulated activation of the AKT/NF-κB pathway. Importantly, PPP1R14B-deficient tumor suppression could be partially restored by wild-type but not phosphorylated mutant RPS6KA1. Taken together, these findings shed light on the function and mechanism of PPP1R14B in HCC progression, indicating PPP1R14B is a promising molecular target for the treatment of HCC.

Keywords: AKT/NF-κB pathway; Hepatocellular carcinoma; PPP1R14B; Phosphorylation; RPS6KA1.