Abstract 3657: Analysis of the regulation of PD-L1 expression and methyl transferases levels following inhibition of histone deacetylases in cancer cells

Abstract

Abstract Epigenetic alterations are known to play important roles in cancer initiation and progression. Therefore, deregulation of epigenetic modifications is considered as a hallmark of cancer; therefore many components of this process are being explored as therapeutic targets. PD-L1 is expressed in most cancer cells, which confers aggressive growth ability and allows the cancers to escape from the immune system of the body. The effects of PD-L1 are mediated through PD-1, also known as CD279, which is normally expressed on the surface of lymphoid and non-lymphoid derived cells. The binding of PD-L1 to the PD-1 receptor mediates immune checkpoint inhibition to regulate T-cell responses. When we analyzed the levels of PD-L1, the expression was high in HCC827 cells, followed by H460, H1975, H226, SJSA1, and U87MG cells. Treatment of HCC827 cells with SAHA, which is a broad-spectrum HDAC inhibitor, was able to reduce the PD-L1 levels in time and dose dependent manner in HCC827. Also, the PD-L1 levels were found to be negatively correlated to the p21 expression following HDAC inhibition. The qRT-PCR analysis revealed significant decreases in the levels of methyltransferase enzymes such as DNMT3A, DNMT3B, PRMT1, SUV39H1, KAT6B, NSD1, SETD1B, and WHSC1. Analysis of the protein levels also confirmed significant reductions following treatment with SAHA. While decreasing the levels of the methyltransferases, SAHA treatment was able to increase the levels of acetylated forms of H2B, H3, and H4. Since acetylation mediated unwinding of the DNA is generally responsible for the increased expression of various genes, it is interesting to see a concomitant reduction in the levels of some of the crucial methyltransferases that are known to produce inhibitory effects. It is suspected that the decrease in the PD-L1, PRMT1, SUV39H1, and DNMT3A levels following HDAC inhibition may be mainly due to reduced transcription. However, it is not clear whether p21 has any negative control on the transcription of the affected genes. Additional studies are required to fully understand the actual mechanisms that may be involved in the regulation of PD-L1 and methyltransferases expression by HDAC inhibitors. (This research was supported by the Royal Dames of Cancer Research Inc., Fort Lauderdale, Florida). Citation Format: Umamaheswari Natarajan, Thiagarajan Venkatesan, Theodore L. Mathuram, Jayanta K. Das, Appu Rathinavelu. Analysis of the regulation of PD-L1 expression and methyl transferases levels following inhibition of histone deacetylases in cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3657.