Histone Demethylase

The histones themselves, particularly H3 and H4, are subject to extensive chemical modifications such as phosphorylation, ubiquitination, acetylation, and methylation, which have profound effects on gene expression. The effects of histone methylation, which occurs primarily on arginines and lysines, depend on the site of modifi- cation, the extent of methylation, as well as on additional modifications on the same or neighboring histones. Misregulation of lysine demethylases is frequently observed in cancer, and the diverse natures of the regulatory defects indicate that cellular homeostasis requires a precise balance of histone methylation and demethylation. The first irrefutable evidence that methylation could be dynamically regulated came in 2004 with the discovery of the lysine-specific demethylase LSD1 (also known as KDM1A). Similar to monoamine oxidases (MAOs), LSD1 uses FAD as a cofactor to oxidize the methyl group and hydrolyze it toformaldehyde. LSD1 demethylates H3K4me1/2, but not H3K4me3, or other methylated lysinesin H3 such as H3K20me2. In prostate cancer cells, LSD1 also demethylates H3K9me1/2 when complexed to the androgen receptor, and other LSD1 variants have shown different substrate specificities. In AML, LSD1 represses differentiation markers such as E-cadherin. 
Chemical or genetic inhibition of LSD1 results in differentiation of leukemia cells in vitro, and LSD1 has been suggested to regulate cancer stem cells. Loss of LSD1 expression in some breast cancers up-regulates transforming growthfactor b (TGF-b), promoting cellular invasion, whereas overexpression of KDM5B (PLU-1) represses genes that promote differentiation and maintenance of genome integrity, such as CAV-1 and BRCA-1. In prostate cancer, KDM4B overexpression promotes cell proliferation by targeting cell cycle regulators such as PLK and Aurora kinase A. Given the therapeutic potential of targeting histone methylation in cancer and other diseases, many research groups are pursuing the development of demethylase inhibitors.


1.Jambhekar A, et al. Cold Spring Harb Perspect Med. 2017;7(1):a026484.