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Overexpression of histone deacetylase (HDAC) may contribute to epigenetic dysregulation in multiple myeloma1

HDAC overexpression and deacetylation closes the chromatin structure and contributes to aberrant gene expression in cancer1

Commonalities in different types of cancers, including haematologic cancers such as multiple myeloma, suggest hypoacetylation of histones due to overexpression of HDACs may play a role in cancer cell survival and proliferation.2 The overexpression of HDACs has been identified in multiple cancers.1

HDACs are a class of enzymes that regulates protein function through the removal of acetyl groups from lysine residues, which is known as deacetylation.1 By deacetylating the lysine tails of core histones, they modify the chromatin structure that DNA is coiled around.1 During deacetylation, chromatin is more tightly packed, or in a closed state, which makes the accessibility of DNA limited.1 These modifications to the chromatin structure result in epigenetic modifications, which affects DNA transcription and leads to tumour suppressor gene silencing. Silencing of tumour suppressor genes is a major underlying cause of unregulated cellular proliferation and transformation.1

Inhibition of HDAC affects epigenetic mechanisms to help restore or increase the expression of genes that may play a critical role in the control of tumour growth and survival.3

Epigenetic dysregulation in multiple myeloma

Studies have shown that patients with multiple myeloma with elevated HDAC expression had shorter progression-free survival (PFS) than patients with a lower expression of these enzymes.4

HDAC overexpression, a type of epigenetic modification, may5:

References:

  1. Atadja PW. HDAC inhibitors and cancer therapy. Prog Drug Res. 2011;67:175-195.
  2. Cea M, Cagnetta A, Gobbi M, et al. New insights into the treatment of multiple myeloma with histone deacetylase inhibitors. Curr Pharm Des. 2013;19(4):734-744.
  3. Dimopoulos MA, San-Miguel JF, Anderson KC. Emerging therapies for the treatment of relapsed or refractory multiple myeloma. Eur J Haematol. 2011;86(1):1-15.
  4. Mithraprabhu S, Kalff A, Chow A, et al. Dysregulated class I histone deacetylases are indicators of poor prognosis in multiple myeloma. Epigenetics. 2014;9(11):1511-1520.
  5. Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 2009;280(2):233-241.