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Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem

Yannick D Benoit1, Mavee S Witherspoon, Kristian B Laursen

  • 1Pharmacology Department, Weill Cornell Medical College, NY 10065, USA. yannick.benoit@usherbrooke.ca

Experimental Cell Research
|April 17, 2013
PubMed

Insights

Targeting polycomb repressive complex 2 (PRC2) with EZH2 inhibitors like DZNep may offer a new epigenetic therapy for colon cancer stem cells (CCSCs). This approach increases apoptosis in CCSCs, suggesting a potential strategy against metastatic colon cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Colorectal cancer is a leading cause of cancer death in the USA.
  • Polycomb repressive complex 2 (PRC2), with SUZ12 and EZH2, is a key epigenetic regulator in digestive epithelia and implicated in various cancers.
  • PRC2 promotes adverse effects in human cancers, including colon cancer.

Purpose of the Study:

  • To investigate the therapeutic potential of inhibiting PRC2 activity in colon cancer stem cells (CCSCs).
  • To evaluate the effects of SUZ12 knockdown and EZH2 inhibition on CCSC apoptosis and survival.

Main Methods:

  • Utilized colon cancer stem cells (CCCSCs) derived from human primary colorectal tumors.
  • Performed SUZ12 knockdown experiments.
  • Treated cells with DZNep, a potent EZH2 inhibitor.

Main Results:

  • SUZ12 knockdown and DZNep treatment significantly increased apoptosis in CCSCs.
  • Decreased Akt phosphorylation was observed in treated CCSCs.
  • Embryonic stem (ES) cell survival remained unaffected.
  • DZNep treatment led to increased PTEN expression in CCSCs.

Conclusions:

  • Pharmacological inhibition of PRC2 histone methyltransferase activity presents a novel epigenetic therapeutic strategy.
  • This strategy specifically targets highly tumorigenic and metastatic colon cancer stem cells.
  • Targeting PRC2 may offer a new avenue for treating advanced colorectal cancer.

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