Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A.
Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent. Inhibition of the histone acetyltransferase (HAT) activity of p300 by a water-soluble, small molecule inhibitor, Hydrazinocurcumin (CTK7A), substantially reduced the xenografted oral tumor growth in mice. These results, therefore, not only establish an epigenetic target for oral cancer, but also implicate a HAT inhibitor (HATi) as a potential therapeutic molecule.
Arif
Mohammed
M
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Jakkur PO, Bangalore-560 064, Karnataka, India.
Vedamurthy
Bhusainahalli M
BM
Choudhari
Ramesh
R
Ostwal
Yogesh B
YB
Mantelingu
Kempegowda
K
Kodaganur
Gopinath S
GS
Kundu
Tapas K
TK
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D012995:Solubility; D015854:Up-Regulation / Q000187:drug effects; D014867:Water / Q000737:chemistry*; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D003474:Curcumin; D004791:Enzyme Inhibitors; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D051548:Histone Acetyltransferases; D006657:Histones; D006834:Hydrazines; D009569:Nitric Oxide; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D014867:Water; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; C475807:hydrazinocurcumin