On November 21st, Cancer Research published online the latest research achievements of Professor Li Feng’s team from the School of Basic Medical Sciences of WHU. The research reveals for the first time the regulation of histone demethylase on retrotransposons. From the perspective of the genome instability, it also explains the primary oncogenic mechanism of KDM4B overexpressing in different tumors.
This is another article in Cancer Research of Professor Li Feng's research team, following the first in this January.
This paper is titled Histone demethylase KDM4B promotes DNA damage by activating long interspersed nuclear element-1. Xiang Ying, a doctoral student of the School of Basic Medical Sciences, is the first author of the paper, with Professor Li Feng as the corresponding author, and Lv Xiangmei, a researcher in Beijing Institute of Genomics of Chinese Academic of Sciences (CAS) as the co-corresponding author. The School of Basic Medical Sciences of WHU is the first author affiliation. The research was supported by the Major Research Plan of the National Natural Science Foundation of China (NSFC), General Program of the NSFC, and Strategic Priority Research Program of the CAS.
There is a type of repeated sequence called transposons that can “jump” in genomes of higher organisms. Amplifying or changing positions in the long historical evolution play an important role in the evolution of the genomes. One type of RNA transposons, also known as retrotransposons, is transposed by RNA. Its replication is often described as a “copy-and-paste” model, that is, the retrotransposon first synthesizes an RNA intermediate by transcription and then uses this RNA as a template to reverse transcribe and synthesize DNA into other locations in the genome. Recent studies have shown that retrotransposons have increased copy number and are more active in tumor tissues, but their regulatory mechanisms and biological functions are not clear.
In recent years, the role of histone demethylase in the development of tumors has attracted more attention. The histone demethylase KDM4B can catalyze the demethylation of H3K9me3 and is frequently over-expressed in various cancer types including breast cancer, colon cancer, ovarian cancer, lung cancer and prostate cancer. In this study, Professor Li Feng's research team assessed whole-genome H3K9me3 distribution in cancer cells and found that H3K9me3 is largely enriched in long interspersed nuclear element-1 (LINE-1). And a significant proportion of KDM4B-dependent H3K9me3 is located in evolutionarily young LINE-1 elements. Furthermore, KDM4B overexpression enhances LINE-1 retrotransposition efficacy, copy number, and associates DNA damage, presumably via the histone demethylase activity of KDM4B. The use of KDM4B inhibitor significantly reduces DNA damage mediated by LINE-1. The research suggests an unexpected oncogenic role for KDM4B overexpression in tumorigenesis, providing clues for the development of new cancer prevention strategies and targeted therapies.
(Author: Jiang Ming. Rewritten by Liang Guoying, Edited by Zheng Lingling, Shen Yuxi and Hu Sijia)