Abstract IA012: Recent progress with PTEN

Abstract

Abstract PTEN is one of the most frequently mutated genes in cancer and is frequently mutated in endometrial carcinoma. Recent progress on PTEN will be presented from our laboratory regarding its role in metabolism, RNA polymerase II transcription, and its expression in tumors with p53 mutations. I) Loss of PTEN activates metabolism of glutamine to pyrimidine and inactivates the ATR DNA damage checkpoint elicited when pyrimidine synthesis is interrupted, which leads to DNA damage and cell death suggesting a metabolic strategy for cancer treatment. II) PTEN in the nucleus binds to RNA polymerase II as wells as CDK7 and CDK9 on chromatin at promoters and regulates RNA Pol II transcription of genes involved in cellular metabolism. Mutation of PTEN increases RNA poly II levels and phosphorylation and increases sensitivity to inhibition of CDK7 and CDK9. III) Mutation of p53 is associated with reduced expression of PTEN and other tumor suppressor genes in many forms of cancer. p53 was found to bind to a dozen tumor suppressor genes in its wild type state and activates their expression under basal low stress conditions when the level of p53 is at a low level. All of these tumor suppressor genes had p53 binding elements in their promoters and enhancers and deletion of the element in a PTEN enhancer lowered its expression. These findings suggest that p53 mediates tumor suppression by maintaining the expression of other tumor suppressor genes including PTEN. Citation Format: Ramon E. Parsons. Recent progress with PTEN [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA012.