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Role of histone chaperone Nucleophosmin‐mediated transcriptional regulation in oral tumorigenesis
Author(s) -
Dey Suchismita,
Senapati Parijat,
Bhattacharya Aditya,
Sudarshan Deepthi,
Das Sadhan,
Kumar Manoj,
Kodaganur Gopinath S.,
Maleikal Tessy Thomas,
Kundu Tapas K.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.458.7
Subject(s) - rna polymerase ii , cancer research , biology , chromatin , chromatin immunoprecipitation , nucleophosmin , carcinogenesis , microbiology and biotechnology , promoter , gene expression , genetics , gene , myeloid leukemia
Histone chaperones regulate the histone traffic in the cell and are involved in different cellular processes including transcription regulation. Nucleophosmin (NPM1), a histone chaperone, enhances acetylation‐dependent chromatin transcription. Acetylation of NPM1 by lysine acetyltransferase (KAT) p300 further enhances its histone chaperone activity and transcription activation potential. Moreover, the acetylated pool of NPM1 (AcNPM1) colocalizes with RNA Polymerase II foci in the nucleus, indicating its role in transcription. NPM1 is also a potent inducer of autoacetylation of p300 thereby enhancing its KAT activity. In the context of cancers, NPM1 is overexpressed in several solid tumors including oral squamous cell carcinoma and regulates genes implicated in oral cancer. AcNPM1 levels are also elevated with increasing grades of oral cancer. However, the precise role of AcNPM1 and the mechanism of transcription regulation by NPM1 are unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP‐seq) to identify the genome‐wide localization of AcNPM1 on chromatin. Interestingly we find that AcNPM1 is enriched on promoters of genes that are co‐occupied by RNA Polymerase II and other histone modifications related to active transcription. RNA‐sequencing after NPM1 knockdown in an oral cancer cell line revealed that NPM1 regulates the expression of genes involved in oral tumorigenesis. Inducible knockdown of NPM1 in an orthotopic mouse model also validates our finding that NPM1 indeed is involved in oral cancer manifestation. These results provide insights into the gene network regulated by NPM1 and AcNPM1 and the possible role of its overexpression and hyperacetylation in oral cancer. In the same context, the underlying mechanisms of transcriptional activation by NPM1/AcNPM1 and the role of NPM1 in the process of tumorigenesis are also currently under investigation. Support or Funding Information Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Sir JC Bose Fellowship, Department of Science and Technology (DST), India (Grant No. SR/S2/JCB‐28/2010), Department of Biotechnology (DBT), India (Programme Support on ‘Chromatin and Disease’, Grant No. BT/01/CEIB/10/III/01 and Virtual National Oral Cancer Institute, Grant No. BT/PR17576/MED/30/1690/2016) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .