Abstract 815: Regulation of p53 by INPP4B and high fat diet in mouse prostate

Abstract

Abstract Obesity is one of the risk factors for prostate neoplasia development, however the underlying molecular mechanisms that link obesity and prostate cancer remain elusive. The roles of AR, p53, EZH2, INPP4B, and PTEN are implicated in prostate cancer etiology. Androgen receptor (AR) signaling interacts functionally with PTEN, INPP4B, EZH2, and p53 signaling in prostate epithelium, and its transcriptional activity is reprogrammed by changes in the levels of these proteins during prostate cancer progression. Phosphatase and tensin homolog (PTEN) and Inositol Polyphosphate 4-Phosphatase Type-II B (INPP4B) are dual specificity phosphatases which are tumor suppressors in prostate cancer and are lost in nearly half of advanced castration resistant prostate cancers (CRPC). p53 is also a tumor suppressor gene that is frequently inactivated in prostate cancers. Enhancer of Zeste 2 (EZH2) is an epigenetic silencer that increases methylation of histone H3 on K27 and K9 residues and acts as an oncogene in CRPC. We have previously shown that INPP4B inhibits the Akt and PKC signaling pathways, which are activated in obesity. Using an Inpp4b-deficient mouse model, we showed that three-month-old Inpp4b-/- males developed prostatic intraepithelial neoplasia (PIN) when fed a high fat diet (HFD). While the AR protein levels were not altered, the transcriptional activity of AR was reduced in the prostates of Inpp4b-/- males. Furthermore, the prostates of HFD-fed Inpp4b-/- males exhibited increased expression of pro-inflammatory cytokines and macrophage infiltration. It was previously reported that indolent nature of the prostate neoplasia, which is caused by prostate specific Pten knockout, is due to the compensatory increase in other tumor suppressor proteins, such as p53, SMAD4, and PML. Concomitant with Pten, knockout of these individual tumor suppressors led to drastic acceleration of prostate neoplasia. Similar to prostates of Pten-/- mice, p53 levels increased in Inpp4b-/- males fed a low fat diet (LFD). Unlike males fed LFD, p53 protein levels decreased in HFD fed Inpp4b-/- mice, consistent with the development of PIN in this group. EZH2 levels as well as the levels of its targets, H3K27me3 and H3K9me2, decreased in ventral prostates of the Inpp4b-/- males and that decrease was exacerbated by the HFD. Similar to our mouse model, we observed significant positive correlation between the INPP4B and EZH2 expression in the prostates of healthy men and prostate cancer patients. In summary, we showed that loss of INPP4B synergizes with the HFD in reprogramming AR activity, reduction of EZH2 levels, and increases inflammation. Importantly, HFD reverses compensatory increase in p53 protein levels in prostates of Inpp4b-/- males. These alterations contribute to the development of PIN in the prostates of HFD-fed Inpp4b-/- males. Citation Format: Yasemin Ceyhan, Manqi Zhang, Irina U. Agoulnik. Regulation of p53 by INPP4B and high fat diet in mouse prostate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 815.