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.

14-3-3γ prevents centrosome duplication by inhibiting NPM1 function

“…14-3-3γ might inhibit NPM1 function by inhibiting the phosphorylation of NPM1 on T199 by CDK1 or CDK2 as T199 phosphorylation is considerably decreased on the S48E mutant of NPM1 ( figure 5). Another point mutant of NPM1, L18Q (77), that inhibits NPM1 oligomer formation cannot rescue the single centrosome phenotype observed upon D129A expression. Therefore, 14-3-3γ inhibits NPM1 function possibly by inhibiting higher-order oligomer formation and by inhibiting the phosphorylation of NPM1 on T199 by CDK1 or CDK2.…”

14–3‐3γ prevents centrosome duplication by inhibiting NPM1 function

“…The other S125A and S125E mutants of NPM1 did not affect the percentage of cells with a single centrosome in cells expressing D129A (Figure S3a). An oligomerization defective mutant of NPM1 (L18Q (Senapati et al, 2019)) was also unable to decrease the percentage of cells with a single centrosome in D129A expressing cells, suggesting that the oligomerization of NPM1 was required for the ability of NPM1 to regulate centrosome licensing (Figure S3b).…”

“…14-3-3γ might inhibit NPM1 function by inhibiting the phosphorylation of NPM1 on T199 by CDK1 or CDK2 as T199 phosphorylation is considerably decreased on the S48E mutant of NPM1 (Figure 5). Another point mutant of NPM1, L18Q (P. Senapati et al, 2019), that inhibits NPM1 oligomer formation cannot rescue the single centrosome phenotype observed upon D129A expression. Therefore, 14-3-3γ inhibits NPM1 function possibly by inhibiting higher-order oligomer formation and by inhibiting the phosphorylation of NPM1 on T199 by CDK1 or CDK2.…”