TY - JOUR
T1 - Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways
AU - Abou El Hassan, Mohamed
AU - Huang, Katherine
AU - Eswara, Manoja B K
AU - Zhao, Michael
AU - Song, Lan
AU - Yu, Tao
AU - Liu, Yu
AU - Liu, Jeffrey C
AU - McCurdy, Sean
AU - Ma, Anqi
AU - Wither, Joan
AU - Jin, Jian
AU - Zacksenhaus, Eldad
AU - Wrana, Jeffrey L
AU - Bremner, Rod
N1 - Publisher Copyright:
© 2015 Abou El Hassan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2015
Y1 - 2015
N2 - Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment.
AB - Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment.
KW - Cell Line, Tumor
KW - Cytokines/metabolism
KW - DNA Helicases/metabolism
KW - Enhancer of Zeste Homolog 2 Protein
KW - Epigenesis, Genetic/drug effects
KW - Gene Knockdown Techniques
KW - Genome, Human
KW - Humans
KW - Interferon-gamma/metabolism
KW - Neoplasm Proteins
KW - Neoplasms/immunology
KW - Nuclear Proteins/metabolism
KW - Polycomb Repressive Complex 2/metabolism
KW - Promoter Regions, Genetic/genetics
KW - RNA, Small Interfering/metabolism
KW - Signal Transduction/drug effects
KW - Small Molecule Libraries/pharmacology
KW - Transcription Factors/metabolism
UR - http://www.scopus.com/inward/record.url?scp=84935022141&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0126466
DO - 10.1371/journal.pone.0126466
M3 - Article
C2 - 26030458
SN - 1932-6203
VL - 10
SP - e0126466
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e0126466
ER -
