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Renal Cancer
Published in Dongyou Liu, Tumors and Cancers, 2017
Specific genetic mutations include PBRM1, BAP1, SETD2, KDM5a, ARID1a, UTX, PIK3CA, PTEN, and MTOR in clear cell RCC; MET and the fumarate hydratase (FH) gene in papillary RCC; and losses of whole chromosomes 1, 2, 6, 10, 13, 17, and 21, and mutations in PTEN (at 10q23) and TP53 (at 17p13) in chromophobe RCC [4,5].
Aging Epigenetics
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Vasily V. Ashapkin, Lyudmila I. Kutueva, Boris F. Vanyushin
A genome-wide RNAi screen for genes that regulate life span in C. elegans resulted in a number of genes encoding the SET domain containing histone methyltransferases [45]. Knockdown of set-2, set-4, set-9, set-15, and ash-2 extended the worm life span, ash-2 having the most significant effect. The encoded protein ASH-2 is a member of H3K4 trimethylation (H3K4me3) complex in yeast, flies, and mammals. In C. elegans, ash-2 knockdown decreases global H3K4me3 levels. WDR-5 is a protein that interacts with ASH-2 in mammals, and is important for the mono-, di-, and trimethylation of H3K4 both in C. elegans and mammals. The wdr-5 knockdown also decreases H3K4me3 levels and significantly (by ∼30%) extends life span in C. elegans. Thus, ASH-2 and WDR-5 mediated H3K4 trimethylation seems to promote aging and limit the life span in C. elegans. In mammals, ASH-2 and WDR-5 form a complex with several H3K4me3 methyltransferases of the SET1/MLL family. Of the four SET1/MLL orthologues in C. elegans, SET-1, SET-2, SET-12, and SET-16, only SET-2 affects the life span. The set-2 knockdown worms have reduced H3K4me3 levels. On the other hand, neither set-9 nor set-15 knockdowns affect global H3K4me3 levels, even though they both regulate the life span. The bacterially expressed SET-2 methyltransferase methylates histone H3 at lysine 4 in vitro to generate H3K4me2, whereas ASH-2 converts H3K4me2 to H3K4me3. Analysis of the life span-extending effects of combined mutations showed that ASH-2, WDR-5, and SET-2 act in the same pathway to limit the life span. RBR-2 is an H3K4me3 demethylase homologous to the human KDM5A and KDM5B—H3K4me3 demethylases of the JARID family. The rbr-2 mutant worms show increased H3K4me3 levels and a significantly decreased life span, indicating that RBR-2 activity is necessary for normal longevity. The ash-2 knockdown leads to changes in the expression of 220 genes at the larval stage L3 and of 847 genes at D5 (day 5) of adulthood. This set of ASH-2-controlled genes is most enriched for genes known to affect the life span and to change expression during aging. These results show that members of the H3K4me3 methyltransferase complex ASH-2 and of the H3K4me3 demethylase complex RBR-2 regulate aging by controlling the expression of a specific subset of genes.
Molecular insights into cancer drug resistance from a proteomics perspective
Published in Expert Review of Proteomics, 2019
Yao An, Li Zhou, Zhao Huang, Edouard C. Nice, Haiyuan Zhang, Canhua Huang
ITH has increasingly being described as the root cause of therapy resistance. In a recent study, researchers demonstrated that endocrine resistance in breast cancer is associated with higher transcriptomic heterogeneity, which was confirmed by CyTOF. This experiment identified KDM5A/B as key regulators of this process, suggesting that ITH can be decreased by modulating the activity of epigenetic enzymes, such as KDM5 family members, ultimately leading to improved responses to treatment [115]. Glioblastoma (GBM) is a highly aggressive brain tumor, in which therapy resistance and disease relapse are inevitable. Because of the heterogeneous landscape of GBM, CyTOF was employed to investigate the key proteins and signaling pathways that confer therapeutic resistance. In temozolomide (TMZ)-resistant GBM, analysis of single-cell derived clonal populations identified differential EGFR expression and DNA repair pathways [116,117]. These results suggest that CyTOF could be an important approach for exploring the mechanisms of cancer drug resistance derived by ITH.
Biology and targeting of the Jumonji-domain histone demethylase family in childhood neoplasia: a preclinical overview
Published in Expert Opinion on Therapeutic Targets, 2019
Tyler S. McCann, Lays M. Sobral, Chelsea Self, Joseph Hsieh, Marybeth Sechler, Paul Jedlicka
JHDMs are most readily targetable through their JmjC domain-dependent demethylase enzymatic activity. Whether this is the optimal approach in a given cancer depends on demonstration that such activity is critical to phenotypic effects and control of expression of key downstream genes. For many JHDMs, this information remains to be determined, both in adult and pediatric cancers. Further, all JHDMs are multi-domain proteins, as summarized in Table 1. However, at this time, the role of most of these additional domains in gene regulation, and normal and abnormal biology, including cancer, largely remains to be defined. A case in point illustrating both of the above-unanswered questions is KDM5A. Canonically a repressor of gene expression via its H3K4 demethylase activity, KDM5A has been shown to be able to activate gene expression both in normal and cancer cells, including pro-metastatic genes in the case of the latter. Mechanistic studies addressing gene activation have identified potential roles for both demethylase-dependent as well as independent mechanisms. With regard to the demethylase-independent mechanisms of gene activation, the structural/functional domains responsible have, in most cases, not been defined; moreover, some studies have suggested an unexpected role for the demethylase activity in gene activation. Lastly, on a broader level, the precise role of H3K4 methylation as a determinant of gene regulatory element activity is at present incompletely understood [28]. Thus, at this point, optimal strategies for therapeutic targeting of JHDMs in cancer in many cases await further information on molecular mechanisms of action.
Small molecule KDM4s inhibitors as anti-cancer agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Hongzhi Lin, Qihang Li, Qi Li, Jie Zhu, Kai Gu, Xueyang Jiang, Qianqian Hu, Feng Feng, Wei Qu, Yao Chen, Haopeng Sun
After KDM4 subfamily, the roles of KDM5 subfamily in cancer have attracted increasingly attention recently119. Especially, KDM5A and 5B could promote the development of drug tolerance and maintain tumour-initiating cells. Many evidences indicate that KDM5s are potential targets for cancer therapy. Meanwhile, many KDM5 selective inhibitors have been disclosed as anticancer agents.