The emerging roles of lysine-specific demethylase 4A in cancer:Implications in tumorigenesis and therapeutic opportunities

Lysine-specific demethylase 4 A(KDM4A,also named JMJD2A,KIA0677,or JHDM3A)is a demethylase that can remove methyl groups from histones H3K9me2/3,H3K36me2/3,and H1.4K26me2/me3.Accumulating evidence suggests that KDM4A is not only involved in body homeostasis(such as cell proliferation,migration and differentiation,and tissue development)but also associated with multiple human diseases,especially cancers.Recently,an increasing number of studies have shown that pharmacological inhibition of KDM4A significantly attenuates tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia.Although there are several reviews on the roles of the KDM4 subfamily in cancer development and therapy,all of them only briefly introduce the roles of KDM4A in cancer without systematically summarizing the specific mechanisms of KDM4A in various physiological and pathological processes,especially in tumorigenesis,which greatly limits advances in the understanding of the roles of KDM4A in a variety of cancers,discovering targeted selective KDM4A inhibitors,and exploring the adaptive profiles of KDM4A antagonists.Herein,we present the structure and functions of KDM4A,simply outline the functions of KDM4A in homeostasis and non-cancer diseases,summarize the role of KDM4A and its distinct target genes in the development of a variety of cancers,systematically classify KDM4A inhibitors,summarize the difficulties encountered in the research of KDM4A and the discovery of related drugs,and provide the corresponding solutions,which would contribute to understanding the recent research trends on KDM4A and advancing the progression of KDM4A as a drug target in cancer therapy.

The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation

Interleukin(IL)17-producing T helper(Th17)cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases,such as multiple sclerosis,psoriasis,and ulcerative colitis.Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently,the participation of epigenetic modifications in the differentiation process has yet to be elucidated.We demonstrated here that histone H3 lysine-27(H3K27)demethylation,predominantly mediated by the H3K27 demethylase Jmjd3,crucially regulated Th17 cell differentiation.Activation of naı¨ve CD41 T cells immediately induced high expression of Jmjd3.Genetic depletion of Jmjd3 in CD41 T cells specifically impaired Th17 cell differentiation both in vitro and in vivo.Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficientCD41 T cells.Importantly,Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis(EAE).Furthermore,inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro.At the molecular level,Jmjd3 directly bound to and reduced the level of H3K27 trimethylation(me3)at the genomic sites ofRorc,which encodes the masterTh17 transcription factorRorgt,and Th17 cytokine genes such as Il17,Il17f,and Il22.Therefore,our studies established acritical role of Jmjd3-mediatedH3K27demethylation inTh17 cell differentiation andsuggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.

Zinc-finger protein GmZF351 improves both salt and drought stress tolerance in soybean

Abiotic stress is one of the most important factors reducing soybean yield. It is essential to identify regulatory factors contributing to stress responses.A previous study found that the tandem CCCH zincfinger protein Gm ZF351 is an oil level regulator. In this study, we discovered that the Gm ZF351 gene is induced by stress and that the overexpression of Gm ZF351 confers stress tolerance to transgenic soybean. Gm ZF351 directly regulates the expression of Gm CIPK9 and Gm SnRK, leading to stomata closing, by binding to their promoter regions, which carry two CT(G/C)(T/A)AA elements.Stress induction of Gm ZF351 is mediated through reduction in the H3K27me3 level at the Gm ZF351locus.TwoJMJ30-demethylase-likegenes,Gm JMJ30-1 and Gm JMJ30-2, are involved in this demethylationprocess.Overexpressionof Gm JMJ30-1/2 in transgenic hairy roots enhances Gm ZF351 expression mediated by histone demethylation and confers stress tolerance to soybean.Yield-related agronomic traits were evaluated in stable Gm ZF351-transgenic plants under mild drought stress conditions. Our study reveals a new mode of Gm JMJ30-Gm ZF351 action in stress tolerance, in addition to that of Gm ZF351 in oil accumulation. Manipulation of the components in this pathway is expected to improve soybean traits and adaptation under unfavorable environments.

Non-homologous functions of the AlkB homologs

TheDNArepair enzyme AlkB was identified in E.coli more than three decades ago.Since then,nine mammalian homologs,all members of the superfamily of alpha-ketoglutarate and Fe(II)-dependent dioxygenases,have been identified(designated ALKBH1–8 and FTO).While E.coli AlkB serves as a DNA repair enzyme,only two mammalian homologs have been confirmed to repair DNA in vivo.The other mammalian homologs have remarkably diverse substrate specificities and biological functions.Substrates recognized by the different AlkB homologs comprise erroneous methyl-and etheno adducts in DNA,unique wobble uridine modifications in certain tRNAs,methylated adenines in mRNA,and methylated lysines on proteins.The phenotypes of organisms lacking or overexpressing individual AlkB homologs include obesity,severe sensitivity to inflammation,infertility,growth retardation,and multiple malformations.Here we review the present knowledge of the mammalian AlkB homologs and their implications for human disease and development.