Abstract 1986: p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit

Abstract

PP2A holoenzymes are the majority of Ser/Thr phosphatases in human cells and each PP2A complex contains one scaffold subunit, one catalytic subunit, and one regulatory subunit. PP2A regulatory subunits, existing in four sub-families encoded by 15 genes, determine the substrate specificities and intracellular localizations of PP2A. We previously reported an essential role for PR55α, a PP2A regulatory subunit, in the support of malignant potential of pancreatic cancer cells, which includes promoting YAP-activation that supports anchorage-independent growth and metastasis. Furthermore, our data showed that PR55α level is elevated in pancreatic cancer relative to normal tissues and high PR55α levels correlate with poor patient survival. The studies in this report reveal a novel mechanism by which the p53 tumor suppressor negatively regulates PR55α protein stability. The results show that p53 inactivation by siRNA-knockdown, gene-deletion, HPV-E6 promoted degradation, or p53R175H mutant expression all results in the increase of PR55α expression. Subsequent studies demonstrate that this p53 function is mediated through its target gene FBXL20, a substrate recognition component of the SCF (Skp_Cullin_F-box) ubiquitin ligase complex that facilitates proteasomal degradation. As a result, the expression of mutant p53R175H in human pancreatic ductal cells mimics the PR55α effect, increasing c-Myc protein stability, and promoting anchorage-independent proliferation. Additionally, FBXL20 mRNA levels are significantly reduced in pancreatic cancers relative to normal control, and low FBXL20 levels correlate with poor patient survival, both of which inversely resemble the pathological effects of PR55α in pancreatic cancer. Collectively, these results define a novel p53 function in the suppression of PR55α expression. Citation Format: Ying Yan, Lepakshe Madduri, Nichole Brandquist, Chitra Palanivel, Sumin Zhou, Charles Enke, Michel Ouellette. p53/FBXL20 axis negatively regulates the protein stability of PR55α, a PP2A regulatory subunit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1986.