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Molecular and Cellular Biology, September 2009, p. 5115-5127, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01969-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Acetylated NPM1 Localizes in the Nucleoplasm and Regulates Transcriptional Activation of Genes Implicated in Oral Cancer Manifestation{triangledown} ,{dagger}

Jayasha Shandilya,1 Venkatesh Swaminathan,1,{ddagger} Shrikanth S. Gadad,1 Ramesh Choudhari,1 Gopinath S. Kodaganur,2 and Tapas K. Kundu1*

Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, Karnataka, India,1 Bangalore Institute of Oncology, Bangalore 560027, Karnataka, India2

Received 31 December 2008/ Returned for modification 31 January 2009/ Accepted 29 June 2009

Nucleophosmin (NPM1) is a multifunctional protein involved in the regulation of centrosome duplication, ribosome biogenesis, genomic stability, histone chaperone function, and transcription. Overexpression of NPM1 is associated with cancers of diverse histological origins. Here, we have found that p300-mediated acetylation of NPM1 modulates its subcellular localization and augments its oncogenic potential. Acetylated NPM1 is predominantly localized in the nucleoplasm, where it associates with transcriptionally active RNA polymerase II. Deacetylation of NPM1 is brought about by human SIRT1 and reduces its transcriptional activation potential. Remarkably, increased levels of acetylated NPM1 were found in grade II and III oral squamous cell carcinoma (OSCC) patient samples. Small interfering RNA (siRNA)-mediated knockdown of NPM1 in an OSCC cell line, followed by microarray analysis and chromatin immunoprecipitation experiments, revealed that some of the genes involved in oral cancer malignancy are regulated by NPM1 and have acetylated NPM1 localized at their promoters. Either suppression of p300 by siRNA or mutation of acetylatable lysine residues of NPM1 resulted in reduced occupancy of acetylated NPM1 on the target gene promoter concomitant with its decreased transcript levels. These observations suggest that acetylated NPM1 transcriptionally regulates genes involved in cell survival and proliferation during carcinogenesis.

* Corresponding author. Mailing address: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, Karnataka, India. Phone: 91-80-22082840. Fax: 91-80-22082766. E-mail: tapas{at}jncasr.ac.in

{triangledown} Published ahead of print on 6 July 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Workman Lab, Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110.

Molecular and Cellular Biology, September 2009, p. 5115-5127, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01969-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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