786.6 - Histone chaperone Nucleophosmin regulates transcription of key genes involved in oral tumorigenesis

Tapas Kundu (Jawaharlal Nehru Centre for Advanced Scientific Research), Parijat Senapati (Jawaharlal Nehru Centre for Advanced Scientific Research), Aditya Bhattacharya (Jawaharlal Nehru Centre for Advanced Scientific Research), Sadhan Das (CSIR-Central Drug Research Institute), Suchismita Dey (Jawaharlal Nehru Centre for Advanced Scientific Research), Deepthi Sudarshan (Jawaharlal Nehru Centre for Advanced Scientific Research), Shyla G (Rajiv Gandhi Centre for Biotechnology), Jyoti Vishwakarma (CSIR-Central Drug Research Institute), Surabhi Sudevan (Jawaharlal Nehru Centre for Advanced Scientific Research), Ravishankar Ramachandran (CSIR-Central Drug Research Institute), Tessy Maliekal (Rajiv Gandhi Centre for Biotechnology)

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate acetylation-dependent transcription from chromatin templates in vitro. Acetylation of NPM1 by p300 has been shown to further enhance its transcription activation potential. Moreover, its total and acetylated pools are increased in oral squamous cell carcinoma. However, the role of NPM1 or its acetylated form (AcNPM1) in transcriptional regulation in cells and oral tumorigenesis is not fully elucidated. Using ChIP-seq analyses, we provide the first genome-wide profile of AcNPM1 and show that AcNPM1 is enriched at transcriptional regulatory elements. AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. In addition, using a high-throughput protein interaction profiling approach, we show that NPM1 interacts with RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. NPM1 histone chaperone activity also contributes to its transcription activation potential. Further, NPM1 depletion leads to decreased AcNPM1 occupancy and reduced expression of genes required for proliferative, migratory and invasive potential of oral cancer cells. NPM1 depletion also abrogates the growth of orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator during during RNA polymerase II-driven transcription and regulates the expression of genes that promote oral tumorigenesis.

Funding: This work was supported by JNCASR, Sir JC Bose Fellowship, DST, India (Grant No. SR/S2/JCB-28/2010), 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). PS is supported by the CSIR and, SD2 and AB are supported by the UGC, India, respectively. SD1 is supported by the DBT/Wellcome Trust India Alliance grant (IA/I/19/1/504271 to SD1).