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Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways
Mohamed Abou El Hassan1, Katherine Huang1, Manoja B K Eswara1
1Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada.
Plos One
|June 2, 2015
Summary
Polycomb Repressive Complex 2 (PRC2) epigenetically silences immune genes in cancer cells, distinct from non-cancer cells. Inhibiting PRC2 reactivates these immune pathways, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Epigenetics
- Cancer Biology
- Immunology
Background:
- Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator implicated in tumorigenesis.
- Cancers often evade immune detection through complex regulatory mechanisms.
- The precise role of PRC2 in coordinating immune evasion in cancer remains unclear.
Purpose of the Study:
- To investigate the role of PRC2 in regulating immune pathways within cancer cells.
- To determine if PRC2's function in immune regulation is cancer-selective.
- To explore the therapeutic potential of PRC2 inhibition on immune gene expression.
Main Methods:
- RNA interference (RNAi) and EZH2 inhibitors were used to target PRC2.
- Analysis of cytokine, cytokine receptor, and IFNγ stimulated gene (ISG) expression.
- Chromatin immunoprecipitation (ChIP) to assess H3K27me3 and H3K4me3 marks.
- Assessment of immune gene induction in the presence and absence of SWI/SNF.
Main Results:
- PRC2 was found to repress hundreds of cytokine and ISG genes in a cancer-selective manner.
- The repertoire of PRC2-repressed immune genes varied significantly across different cancer types.
- PRC2 inhibition, via RNAi or EZH2 inhibitors, activated cytokine/cytokine receptor promoters.
- PRC2 inhibition restored immune gene induction even in SWI/SNF-deficient cancers.
Conclusions:
- PRC2 acts as a higher-order regulator of the immune program in cancer cells.
- PRC2 inhibition enhances cancer cell responsiveness to immune signals.
- This newly identified PRC2 function has significant implications for EZH2 inhibitor-based cancer therapies.
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