Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers

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Lili Li1, Chen Li1, Haitao Mao1

  • 1Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong.

Scientific Reports
|May 27, 2016
PubMed

Insights

TET1, a crucial gene demethylase, is frequently silenced by methylation in various cancers, acting as a tumor suppressor by reactivating silenced tumor suppressor genes.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Promoter CpG methylation regulates gene expression.
  • TET proteins are CpG demethylases; loss of 5-hydroxymethylcytosine (5hmC) is an epigenetic hallmark of cancer.
  • TET proteins play critical roles in epigenetic tumorigenesis.

Purpose of the Study:

  • To investigate TET1 as a potential tumor suppressor in various cancers.
  • To identify the mechanism of TET1 inactivation in tumorigenesis.
  • To explore the therapeutic potential of TET1 in cancer treatment.

Main Methods:

  • Analysis of tumor methylomes to identify TET1 as a methylated target.
  • Confirmation of TET1 downregulation/methylation in cancer cell lines and primary tumors.
  • Ectopic expression of TET1 catalytic domain in tumor cells.
  • Assessment of TET1 demethylase activity in cancer cells and its effect on tumor suppressor gene promoters.

Main Results:

  • TET1 was found to be frequently downregulated and methylated in multiple carcinomas and lymphomas.
  • Ectopic expression of TET1 suppressed tumor cell growth and induced apoptosis.
  • TET1 catalytic domain exhibited demethylase activity, inhibiting CpG methylation of tumor suppressor gene promoters (e.g., SLIT2, ZNF382, HOXA9) and reactivating their expression.
  • Epigenetic silencing, not mutation, is the dominant mechanism for TET1 inactivation in cancers.

Conclusions:

  • TET1 functions as a broad tumor suppressor across various cancer types.
  • Epigenetic silencing of TET1 contributes to tumorigenesis by promoting CpG methylation.
  • TET1 inactivation creates a feedback loop of CpG methylation during cancer development.

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