Transcriptional Repression of Histone Deacetylase 3 by the Histone Demethylase KDM2A Is Coupled to Tumorigenicity of Lung Cancer Cells

Abstract

Background: Overexpression of the epigenetic repressor KDM2A promotes lung tumorigenesis. Results: Transcriptional inhibition of HDAC3 expression by KDM2A releases cell cycle and proinvasive genes from HDAC3-mediated repression and positively regulates cell proliferation and invasiveness. Conclusion: KDM2A-mediated repression of HDAC3 is linked to KDM2A-promoted tumorigenicity. Significance: Our findings provide a novel epigenetic insight into how KDM2A promotes lung tumorigenesis and have implications for therapeutic intervention.

A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner

“…2,[6][7][8] Although H3K36me3 and H3K36me2 are associated mainly with active gene bodies, where they prevent spurious transcription initiations, H3K36me2 has been also found to be associated with transcriptionally active gene promoters and its removal by KDM2A leads to transcriptional repression of such promoters. 1,[9][10][11][12][13][14][15][16][17][18][19] The short demethylation-defiecient KDM2A isoform KDM2A-SF lacks the N-terminal demethylation domain, but it retains the ability to bind to CpG islands. 15,23,24 KDM2A-SF is therefore likely to compete with KDM2A-LF for the same CpG islands.…”

“…20,21 KDM2A has been found to be misregulated in various cancers and its loss-of-function mouse mutants are embryonically lethal. 16,17,22 As opposed to the full length "long form" KDM2A protein (KDM2A-LF), which contains all the functional domains, the "short form" KDM2A protein (KDM2A-SF), lacks the N-terminal JmjC demethylation domain and therefore it is unable to function as a demethylase. 15,23,24 KDM2A is known to directly interact with the heterochromatin protein HP1a and the KDM2A amino acid motif necessary for this interaction is also present in KDM2A-SF.…”

“…2,[9][10][11][12][13][14][15] Demethylation of promoter-associated H3K36me2 by KDM2A has been shown to result in transcriptional repression of these promoters, whereas a loss of KDM2A leads to increased levels of promoter-associated H3K36me2 and transcriptional de-repression of these promoters. 10,14,[16][17][18][19] KDM2A also demethylates lysine residues of non-histone proteins such as the NF-kB p65 subunit or b-catenin. 20,21 KDM2A has been found to be misregulated in various cancers and its loss-of-function mouse mutants are embryonically lethal.…”

Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7

“…The enzyme has been reported to be involved in the regulation of NF‐κB signalling17 and the control of stem‐cell differentiation and proliferation 18. Its overexpression in gastric and small‐cell lung cancer cells suggests that inhibiting KDM2A may represent a strategy for targeting certain cancers at the transcription level 19, 20. All KDM2A inhibitors described to date are 2‐OG competitors, and none are truly selective.…”

A New Cell Counting Method to Evaluate Anti-tumor Compound Activity

“…The acetylation and deacetylation of histones and non-histone proteins by histone acetylases and HDACs play important roles in gene expression regulation and transcription (Chueh et al, 2014;Dhar et al, 2014). The effects of acetylation and deacetylation include signal transduction, protein phosphorylation, cell cycle, proliferation, apoptosis, and cardiac development (Wang et al, 2014;Zhang et al, 2014).…”