Abstract PR03: Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and Lung Cancer

Abstract

Abstract Dysregulated epigenetic control of lung lineage fate is believed to be a major driver of lung disease, including plasticity in lung cancer. Our laboratory has observed a marked decrease in Polycomb Repressive Complex 2 (PRC2) activity in bronchiolar epithelium of COPD patients, poorly differentiated adenocarcinomas and the majority of squamous cell carcinomas. Interestingly, the PRC2 methyltransferase EZH2 is still highly expressed in many of these tissues, suggesting a de-coupling of EZH2 and PRC2 activity. A mouse model of lineage switching from adenocarcinoma to squamous lung cancer clearly showed that loss of PRC2 activity was a catalyst to epigenetic reprogramming. This model also showed increased infiltration of neutrophils, which are known to produce large amounts of superoxide. Our current hypothesis is that oxidative stress, in part through neutrophil recruitment to lung tissue, drives the loss of PRC2 activity through metabolic changes. To support this hypothesis, we have shown that a redox-sensitive enzyme in the methionine pathway, cystathionine beta synthase (CBS), is expressed in COPD and lung cancer and modulates PRC2 activity. Enforced CBS expression drives global decrease in the PRC2-mediated histone marked, H3K27me3, and increased expression of genes expressed by basal cells of the lung, including KRT5, SOX2 and PD-L1. Furthermore, we have found that PRC2 activity can be stabilized through restriction of methionine levels or knock-down of CBS, leading to increased sensitivity of cells to chemotherapy and radiation treatments. PRC2-low epigenetic states can also be exploited – either pharmacological or genetic perturbation of EZH2 led to sensitivity to several classes of drugs, including immunotherapies. Our future studies include using Stable Isotope Resolved Metabolomics (SIRM) to understand how oxidative stress alters the methionine cycle and ultimately changes the stability and function of the PRC2 complex, and to use this information to design better therapeutic strategies. Work supported by AACR Innovation and Discovery Grant, American Cancer Society 133123-RSG-19-081-01-TBG and IRG-85-001-25, NCI R01 CA237643, NIGMS P20 GM121327-03, NIEHS T32 5T32ES007266-30, NCI T32 CA165990 and NHLBI F31 HL151111-01. Citation Format: Mojtaba Bakhtiari, Aria L. Byrd, Fan Chen, Alexsandr Lukyanchuk, Tanner J. DuCote, Christine Fillmore Brainson. Metabolic control of Polycomb Repressive Complex 2 in Lung Disease and Lung Cancer [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR03.