TY - JOUR
T1 - PD-L1 Expression in Human Breast Cancer Stem Cells Is Epigenetically Regulated through Posttranslational Histone Modifications
AU - Darvin, Pramod
AU - Sasidharan Nair, Varun
AU - Elkord, Eyad
N1 - Publisher Copyright:
© 2019 Pramod Darvin et al.
PY - 2019
Y1 - 2019
N2 - Tumor progression through immune evasion is a major challenge in cancer therapy. Recent studies revealed that enhanced PD-L1 expression in cancer stem cells is linked to immune evasion. Understanding the mechanisms behind this PD-L1 overexpression in cancer stem cells is critical for developing more effective strategies for preventing immune evasion and increasing the efficacy of anti-PD-1/PD-L1 therapy. Tumorsphere formation in breast cancer cells enhanced epithelial to mesenchymal transition (EMT), which is evident by increased expression of mesenchymal markers. In this study, we analyzed CpG methylation of PD-L1 promoter in MCF-7 and BT-549 breast cancer cells and tumorspheres derived from them. PD-L1 promoter was significantly hypomethylated in MCF-7 tumorspheres, but not from BT-549 tumorspheres, compared with their cell line counterparts. The active demethylation of PD-L1 promoter was confirmed by the increase in the distribution of 5hmC and decrease in 5mC levels and the upregulation of TET3 and downregulation of DNMTs enzymes in MCF-7 tumorspheres, compared with the cell line. Additionally, we checked the distribution of repressive histones H3K9me3, H3K27me3, and active histone H3K4me3 in the PD-L1 promoter. We found that distribution of repressive histones to the PD-L1 promoter was lower in tumorspheres, compared with cell lines. Moreover, an overexpression of histone acetylation enzymes was observed in tumorspheres suggesting the active involvement of histone modifications in EMT-induced PD-L1 expression. In summary, EMT-associated overexpression of PD-L1 was partially independent of promoter CpG methylation and more likely to be dependent on posttranslational histone modifications.
AB - Tumor progression through immune evasion is a major challenge in cancer therapy. Recent studies revealed that enhanced PD-L1 expression in cancer stem cells is linked to immune evasion. Understanding the mechanisms behind this PD-L1 overexpression in cancer stem cells is critical for developing more effective strategies for preventing immune evasion and increasing the efficacy of anti-PD-1/PD-L1 therapy. Tumorsphere formation in breast cancer cells enhanced epithelial to mesenchymal transition (EMT), which is evident by increased expression of mesenchymal markers. In this study, we analyzed CpG methylation of PD-L1 promoter in MCF-7 and BT-549 breast cancer cells and tumorspheres derived from them. PD-L1 promoter was significantly hypomethylated in MCF-7 tumorspheres, but not from BT-549 tumorspheres, compared with their cell line counterparts. The active demethylation of PD-L1 promoter was confirmed by the increase in the distribution of 5hmC and decrease in 5mC levels and the upregulation of TET3 and downregulation of DNMTs enzymes in MCF-7 tumorspheres, compared with the cell line. Additionally, we checked the distribution of repressive histones H3K9me3, H3K27me3, and active histone H3K4me3 in the PD-L1 promoter. We found that distribution of repressive histones to the PD-L1 promoter was lower in tumorspheres, compared with cell lines. Moreover, an overexpression of histone acetylation enzymes was observed in tumorspheres suggesting the active involvement of histone modifications in EMT-induced PD-L1 expression. In summary, EMT-associated overexpression of PD-L1 was partially independent of promoter CpG methylation and more likely to be dependent on posttranslational histone modifications.
UR - http://www.scopus.com/inward/record.url?scp=85062615829&partnerID=8YFLogxK
U2 - 10.1155/2019/3958908
DO - 10.1155/2019/3958908
M3 - Article
AN - SCOPUS:85062615829
SN - 1687-8450
VL - 2019
JO - Journal of Oncology
JF - Journal of Oncology
M1 - 3958908
ER -