Arif Mohammed, Vedamurthy Bhusainahalli M, Choudhari Ramesh, Ostwal Yogesh B, Mantelingu Kempegowda, Kodaganur Gopinath S, Kundu Tapas K
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, JNCASR, Jakkur PO, Bangalore-560 064, Karnataka, India.
Chem Biol. 2010 Aug 27;17(8):903-13. doi: 10.1016/j.chembiol.2010.06.014.
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.
组蛋白乙酰化改变与包括癌症在内的多种疾病相关。我们在此报告，与大多数癌症不同，在口腔鳞状细胞癌（OSCC；口腔癌）患者样本中发现组蛋白高度超乙酰化。从机制上讲，由核磷蛋白（NPM1）和甘油醛-3-磷酸脱氢酶（GAPDH）诱导的p300过表达以及增强的自身乙酰化导致超乙酰化，这是一氧化氮（NO）信号依赖性的。水溶性小分子抑制剂肼基姜黄素（CTK7A）对p300组蛋白乙酰转移酶（HAT）活性的抑制，显著降低了小鼠体内移植口腔肿瘤的生长。因此，这些结果不仅为口腔癌确立了一个表观遗传靶点，还表明组蛋白乙酰转移酶抑制剂（HATi）是一种潜在的治疗分子。
