KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage.

Laura Castellini,Rie Von Eyben,Amato J Giaccia,Olga V Razorenova,Eui Jung Moon,Adam J Krieg

doi:10.1093/nar/gkw1281

Abstract

The p53 tumor suppressor protein plays a critical role in orchestrating the genomic response to various stress signals by acting as a master transcriptional regulator. Differential gene activity is controlled by transcription factors but also dependent on the underlying chromatin structure, especially on covalent histone modifications. After screening different histone lysine methyltransferases and demethylases, we identified JMJD2B/KDM4B as a p53-inducible gene in response to DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter. JMJD2B induction attenuates the transcription of key p53 transcriptional targets including p21, PIG3 and PUMA, and this modulation is dependent on the catalytic capacity of JMJD2B. Conversely, JMJD2B silencing led to an enhancement of the DNA-damage driven induction of p21 and PIG3. These findings indicate that JMJD2B acts in an auto-regulatory loop by which p53, through JMJD2B activation, is able to influence its own transcriptional program. Functionally, exogenous expression of JMJD2B enhanced subcutaneous tumor growth of colon cancer cells in a p53-dependent manner, and genetic inhibition of JMJD2B impaired tumor growth in vivo. These studies provide new insights into the regulatory effect exerted by JMJD2B on tumor growth through the modulation of p53 target genes.

Highlights

The p53 protein responds to a variety of cellular stresses, including genotoxic damage, hypoxia, nutrient depletion and aberrant proliferative signals through oncogene activation
To assess how broadly JMJD2B was induced by p53 in response to DNA damage, we examined its activation in response to additional genotoxic agents, such as etoposide, 5fluorouracil (5-FU) and ionizing radiation (IR)
The p53 tumor suppressor protein is a major sensor of cellular stresses and, upon activation, it impacts the transcription of several hundreds genes to regulate key cellular processes including cell cycle, DNA repair, apoptosis, senescence, autophagy and metabolism [1,2,3]

Summary

Introduction

The p53 protein responds to a variety of cellular stresses, including genotoxic damage, hypoxia, nutrient depletion and aberrant proliferative signals through oncogene activation. The increase in p53 protein results in the transcriptional regulation of genes involved in mediating key cellular processes, such as DNA repair, cell-cycle arrest, senescence, apoptosis, autophagy and metabolism [1,2,3]. A major component in the regulation of cellular processes by chromatin structure is the post-translational modifications occurring on the N-terminal tails of histones. Such modifications include acetylation, methylation, phosphorylation, ubiquitylation and sumoylation. Each of these modifications influences the structure of chromatin and, depending on the site, the degree and the type of modification, has different functional outcomes [5]. Whereas lysine acetylation of histones usually correlates with transcriptional activation, histone lysine methylation can be associated with either transcriptional activation or repression depending on the residue and degree of methylation

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