Year: 2018
Type: article
Abstract: The p53 tumor suppressor pathway is frequently inactivated in human cancers. However, there are some cancer types without commonly recognized alterations in p53 signaling. Here we report that histone demethylase KDM5A is involved in the regulation of p53 activity. KDM5A is significantly amplified in multiple types of cancers, an event that tends to be mutually exclusive to p53 mutation. We show that KDM5A acts as a negative regulator of p53 signaling through inhibition of p53 translation via suppression of a subgroup of eukaryotic translation initiation genes. Genetic deletion of KDM5A results in upregulation of p53 in multiple lineages of cancer cells and inhibits tumor growth in a p53-dependent manner. In addition, we have identified a regulatory loop between p53, miR-34, and KDM5A, whereby the induction of miR-34 leads to suppression of KDM5A. Thus, our findings reveal a mechanism by which KDM5A inhibits p53 translation to modulate cancer progression.
Source: iScience
Authors: Dongli Hu, Carolyn Jablonowski, Pei-Hsin Cheng, Alaa AlTahan, Chunliang Li, Yingdi Wang, Lance Palmer, Cuixia Lan, Bingmei Sun, Ahmed Abu-Zaid, Yiping Fan, Mark Brimble, Nicolas T. Gamboa, Ramhari C. Kumbhar, David Yanishevski, Kyle M. Miller, Guolian Kang, Gerard P. Zambetti, Taosheng Chen, Qin Yan, Andrew M. Davidoff, Jun Yang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,240
Awards: G1135677791, MECHANISMS OF GENOME MAINTENANCE BY BROMODOMAIN CHROMATIN READER PROTEINS, Development of small molecules to target KDM4B, G37165343, G417336719, Studies of Childhood Solid Tumors, G5775726095, The role of JMJD6 in MYC-mediated neuroblastoma, G8386741907, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2897406322