Regulation of PD-L1 Expression by Histone Deacetylase Inhibitor SAHA in Lung Cancer Cells
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2018, Vol 19, Issue 4
Abstract
The expression of PD-L1 is checkpoint indicator indicative of immunosuppression and cause for poor prognosis in several cancers. The effects of PD-L1 are mediated through its binding to the Programmed Cell Death-1 (PD-1) receptor, which is expressed on lymphoid and non-lymphoid derived cells. The binding of PD-L1 to the PD-1 receptor mediates checkpoint inhibition to regulate peripheral T-cell responses. Therefore, determining the mechanisms of regulation of the PD-L1 expression is very important for understanding the impacts of immu-nosuppressive microenvironment, and is also crucial for the purpose of reactivating the T-cells that can lead to enhanced tumor attack. Therefore, we analyzed relieving the T-cell from the checkpoint inhibition. The expression of PD-L1 was analyzed in various cancer cells and the highest-level of expression was found in HCC827 (Lung Adenocarcinoma) cells followed by H460 (Large Cell Lung Cancer), H226 (Squamous Cell Carcinoma), H1975 (Non-Small Cell Lung Cancer) and H1568 (Non-Small Cell Lung Cancer). Relatively lower level expressions were found in H23 (Non-Small Cell Lung Cancer) and H522 (Non-Small Cell Lung Cancer) cell lines. To determine the effects of HDAC (Histone Deacetylase) inhibitor SAHA (suberoylanilide hydroxamic acid), we analyzed the expression levels of PD-L1 in HCC827 cells. The treatment of SAHA (0.5 - 10 μM) was able to reduce the expression of PD-L1 in dose dependent manner within 24 hrs. In addition to decreasing the expression of PD-L1, SAHA treatment was sable to produce decreases in EGFR and pEGFR levels also in HCC827 cells following SAHA treatment. Treatment of HCC827 cells with SAHA increased the levels of acetyl-H2B, and acetyl-H3. Since acetylation mediated unwinding of the DNA is typically responsible for increased expression of p21/CDKN1A gene, SAHA treatment elevated the levels of p21WAF1/CIP1 also. It is suspected that the decrease in the PD-L1 levels may be due to reduced transcription of the CD274 gene that is coding for PD-L1. However, it is not clear whether the decrease is because of p21WAF1/CIP1mediated negative control on the transcription or due to some other mechanism. In addition to regulating PD-L1 expression in HCC827 cells that were growing in monolayer, SAHA treat-ment for 7 days induced significant reduction in the volume of H1975 cells that were grown as spheroids. Additional studies are required to fully understand the actual mechanisms that may be involved in the regulation of PD-L1 expression in lung cancer cells.
Authors and Affiliations
Umamaheswari Natarajan, Thiagarajan Venkatesan, Jayanta Kumar Das, Appu Rathinavelu
Keywords
Related Articles
- EP ID EP629809
- DOI 10.26717/BJSTR.2019.19.003348
- Views 129
- Downloads 0
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