Abstract B013: Suppression of TET1 expression down-regulates p16 and contributes to the resistance of SWI/SNF LOF tumors to PRC2 inhibition

Abstract

Abstract Polycomb repressive complex 2 (PRC2) drives the expansion of H3K27me3 epigenetic marker and suppress the expression of target genes including tumor suppressors. Activation mutations of EZH2, the catalytic subunit of the PRC2 complex, are thought to be the driver for certain malignancies such as diffused large B cell lymphoma (DLBCL). The SWI/SNF complex remodels nucleosomes to modulate transcription, they are generally considered as tumor suppressors and loss-of-function (LOF) mutations are frequently found across a wide variety of cancers. Many studies suggest that PRC2 is important for the proliferation of tumor cells with SWI/SNF LOF mutations, indeed, EZH2 inhibitor tazemetostat was approved by FDA for epithelioid sarcoma with SWI/SNF subunit SMARCB1 deletion. While not all SWI/SNF LOF tumors respond to PRC2 inhibition, we would like to know what subset of these tumors are sensitive to PRC2 inhibition. In this study, we have developed a potent and selective PRC2 inhibitor BR1763 which blocks the interaction of EED with tri-methylated histone H3 at Lys 27 (H3K27me3) and inhibits cellular H3K27me3 levels. By analyzing the gene expression patterns of BR1763 treated cells, we found that up-regulation of CDKN2A/p16 and down-regulation of E2F downstream gene are essential for cellular response to PRC2 inhibition. Further studies also confirmed that PRC2 inhibition caused P16 up-regulation and induced cell senescence for the sensitive cells. Importantly, suppression of TET1 expression contributes to the resistance to PRC2 inhibition in SWI/SNF LOF tumors, which may be caused by PcG hypermethylation on p16 promoters. TET1 expression, together with SWI/SNF LOF mutation status, can largely predict the sensitivity of tumor cells to PRC2 inhibition. Citation Format: Hailong Zhang. Suppression of TET1 expression down-regulates p16 and contributes to the resistance of SWI/SNF LOF tumors to PRC2 inhibition. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B013.