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Inactivation of a histone methyltransferase by mutations in human cancers

Keun-Cheol Kim1, Liqing Geng, Shi Huang

  • 1Program in Cancer Genetics and Epigenetics, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.

Cancer Research
|November 25, 2003
PubMed

Insights

Histone methyltransferase (HMT) enzymes, including RIZ1, suppress tumors by methylating histone H3. Mutations and methyl donor deficiency impair this crucial HMT activity, potentially leading to cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Histone methyltransferases (HMTs) possess a catalytic SET domain, homologous to the PR domain.
  • The PR/SET domain is crucial for tumor suppression, but its specific role remains unclear.

Purpose of the Study:

  • To investigate whether histone methyltransferase activity underlies the tumor suppression function of the PR/SET domain.
  • To determine the role of RIZ1 (PRDM2) in histone methylation and its connection to cancer.

Main Methods:

  • Assessed histone H3 lysine 9 methylation by RIZ1.
  • Analyzed the impact of PR domain mutations (found in human cancers) on RIZ1 activity.
  • Investigated the effect of S-adenosylhomocysteine and methyl donor deficiency on RIZ1 and H3 lysine 9 methylation.

Main Results:

  • RIZ1 (PRDM2) was shown to methylate histone H3 on lysine 9.
  • Mutations in the PR domain of RIZ1, prevalent in human cancers, reduced its HMT activity.
  • Deficiency in methyl donors or S-adenosylhomocysteine inhibited RIZ1 and other H3 lysine 9 methylation activities.

Conclusions:

  • H3 lysine 9 methylation by PR/SET domain-containing proteins, like RIZ1, has tumor suppression functions.
  • Impaired HMT activity due to mutations or methyl donor deficiency may contribute to carcinogenesis.

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