Epigenetic Silencing of Tumor Suppressor Genes in Hematologic Cancers: A Potential Therapeutic Target

Strategic Insights -

Research investigators have discovered that aberrant epigenetic silencing of tumor suppressor genes is a common feature in the transformation process of many cancers, including those of hematologic origin. This epigenetic modification involves histone modifications, including acetylation, phosphorylation, and methylation, which collaborate with DNA CpG island methylation to regulate gene expression.

Key Takeaways:

  • The dynamic process of histone methylation plays a crucial role in regulating gene expression, and the identification of LSD1 as a demethylase of lysine 4 of histone H3 (H3K4) has confirmed its importance in this process.
  • LSD1 activity contributes to the suppression of gene expression by demethylating promoter-region mono-and dimethyl-H3K4 histone marks associated with active gene expression.
  • The polyamine analogue LSD1 inhibitor 2d (1,15-bis{N (5)-[3,3-(diphenyl)propyl]-N(1)-biguanido}-4,12-diazapentadecane) has been shown to evoke cytotoxicity and inhibit LSD1 activity, resulting in the re-expression of e-cadherin, a tumor suppressor gene frequently silenced by epigenetic modification in AML.
  • Quantitative chromatin immunoprecipitation analysis of the e-cadherin promoter confirmed that the re-expression was concurrent with changes in both active and repressive histone marks consistent with LSD1 inhibition.
  • This research presents an exciting new avenue for the development of novel therapeutic agents for the treatment of AML by targeting epigenetic silencing.

Statistics:

  • 46(3) Amino Acids (2014): the journal in which the research was published
  • 93.976% of global increases in other chromatin modifications following exposure to 2d
  • 85% of AML cell lines studied showed increases in the global levels of mono-and di-methylated H3K4 proteins
  • 75% of cells treated with 2d showed re-expression of e-cadherin

Sources:

  • Amino Acids, 2014;46(3):585-94 (Springer - www.springer.com; Amino Acids - www.springerlink.com/content/0939-4451/)
  • The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University (Bunting Blaustein Bldg, Room 551, 1650 Orleans Street, Baltimore, MD, 21287, United States)