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

Abstract

Nucleophosmin (NPM1) is a multifunctional histone chaperone that can activate RNA Polymerase II-driven chromatin transcription. Acetylation of NPM1 by acetyltransferase 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 is not fully elucidated. Using ChIP-seq analyses, we show that AcNPM1 co-occupies marks of active transcription at promoters and DNase I hypersensitive sites at enhancers. Moreover, NPM1 interacts with proteins involved in transcription, including RNA Pol II, general transcription factors, mediator subunits, histone acetyltransferase complexes, and chromatin remodelers. Moreover, its histone chaperone also contributes to transcriptional activation. We further show that AcNPM1 regulates key genes required for proliferation, migration and invasion potential of oral cancer cells and knockdown of NPM1 mitigates these processes in cells as well as orthotopic tumors in mice. Collectively, these results establish that AcNPM1 functions as a coactivator and regulates the expression of key genes involved in oral tumorigenesis.