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Human EHMT2/G9a activates p53 through methylation-independent mechanism

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posted on 23.11.2016, 15:37 by Miran Rada, Elena Vasileva, Larissa Lezina, Diana Marouco, Alexey V. Antonov, Salvador Macip, Gerry Melino, Nickola A. Barlev
p53 is a critical tumor suppressor in humans. It functions mostly as a transcriptional factor and its activity is regulated by numerous post-translational modifications. Among different covalent modifications found on p53 the most controversial one is lysine methylation. We found that human G9a (hG9a) unlike its mouse orthologue (mG9a) potently stimulated p53 transcriptional activity. Both ectopic and endogenous hG9a augmented p53-dependent transcription of pro-apoptotic genes, including Bax and Puma, resulting in enhanced apoptosis and reduced colony formation. Significantly, shRNA-mediated knockdown of hG9a attenuated p53-dependent activation of Puma. On the molecular level, hG9a interacted with histone acetyltransferase, p300/CBP, resulting in increased histone acetylation at the promoter of Puma. The bioinformatics data substantiated our findings showing that positive correlation between G9a and p53 expression is associated with better survival of lung cancer patients. Collectively, this study demonstrates that depending on the cellular and organismal context, orthologous proteins may exert both overlapping and opposing functions. Furthermore, this finding has important ramifications on the use of G9a inhibitors in combination with genotoxic drugs to treat p53-positive tumors.Oncogene advance online publication, 25 July 2016; doi:10.1038/onc.2016.258.

History

Citation

Oncogene, 2016, in press

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Old Departments Pre 01 Aug 2015/Department of Biochemistry (Pre 01 Aug 2015)

Version

AM (Accepted Manuscript)

Published in

Oncogene

Publisher

Nature Publishing Group

issn

0950-9232

eissn

1476-5594

Acceptance date

23/05/2016

Copyright date

2016

Available date

25/01/2017

Publisher version

http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2016258a.html

Notes

Following the embargo period the above license applies.

Language

en

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