Histone Demethylase KDM5B as a Therapeutic Target for Cancer Therapy

Jose, Anmi; Shenoy, Gautham G.; Rodrigues, Gabriel; Kumar, Naveena A. N.; Munisamy, Murali; Thomas, Levin; Kolesar, Jill; Rai, Ganesha; Rao, Praveen P.N.; Rao, Mahadev

doi:10.3390/cancers12082121

Cited by 32 publications

(38 citation statements)

References 86 publications

(109 reference statements)

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“…KDM5B (also known as JARID1B or PLU-1) was first identified as being upregulated in breast (6,7) and prostate cancer (8). These two types of cancer have been the focus of previous studies in oncogenesis (9,10).…”

Section: Introductionmentioning

confidence: 99%

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

et al. 2021

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Post-translational modification of histones serve a crucial role in the control of gene transcription. Trimethylation of lysine 4 on histone 3 is associated with transcription activation. There are currently six known methylases and six known demethylases that can control the methylation status of this site. Lysine demethylase 5B (KDM5B) is one such demethylase, which can repress gene expression. In particular KDM5B has been found to be overexpressed in a number of cancer types, and small-molecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knock-out mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔA-T rich interaction domain (ΔARID)-KDM5B strain of mice, which have the ARID domain and five amino acids within the Jumonji (Jmj)N domain spliced out from KDM5B, remain viable and fertile. In the present study, ΔARID-KDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos-1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARID-KDM5B structure compared with that in WT-KDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WT-KDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knock-out mice show varying degrees of lethality, these data suggest that KDM5B serves a crucial function in development in a manner that is independent of its demethylase activity.

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Section: Introductionmentioning

confidence: 99%

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

et al. 2021

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“…- KDM5B is overexpressed in cervical cancers and in HNSCC compared to normal tissues [ 99 , 100 ]. High levels of KDM5B are associated with poor prognosis.…”

Section: The Hpv Impact On the Hptms Landscape Of Host Cells In Hnsccmentioning

confidence: 99%

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies

Ghiani

Chiocca

2022

IJMS

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Head and Neck Squamous Cell Carcinoma (HNSCC) is a highly heterogeneous group of tumors characterized by an incidence of 650,000 new cases and 350,000 deaths per year worldwide and a male to female ratio of 3:1. The main risk factors are alcohol and tobacco consumption and Human Papillomavirus (HPV) infections. HNSCC cases are divided into two subgroups, the HPV-negative (HPV−) and the HPV-positive (HPV+) which have different clinicopathological and molecular profiles. However, patients are still treated with the same therapeutic regimens. It is thus of utmost importance to characterize the molecular mechanisms underlying these differences to find new biomarkers and novel therapeutic targets towards personalized therapies. Epigenetic alterations are a hallmark of cancer and can be exploited as both promising biomarkers and potential new targets. E6 and E7 HPV oncoviral proteins besides targeting p53 and pRb, impair the expression and the activity of several epigenetic regulators. While alterations in DNA methylation patterns have been well described in HPV+ and HPV− HNSCC, accurate histone post-translational modifications (hPTMs) characterization is still missing. Herein, we aim to provide an updated overview on the impact of HPV on the hPTMs landscape in HNSCC. Moreover, we will also discuss the sex and gender bias in HNSCC and how the epigenetic machinery could be involved in this process, and the importance of taking into account sex and/or gender also in this field.

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“…For example, the gene KDM38 , a histone H3 lysine 9 demethylase, has been implicated in the progression of primary prostate cancer to metastatic CRPC 78 . Lysine demethylases containing the Jumonji C domain are deregulated in diverse cancer types, including prostate cancer, 79 and have generated enthusiasm as druggable targets 80 . The genomic instability that emerges and propagates during the expansion of malignant clonal prostate cancer cells likely creates a fertile environment for genetic disruption of these chromatin regulators.…”

Section: Bet Proteinsmentioning

confidence: 99%

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

et al. 2022

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In patients with prostate cancer, the duration of remission after treatment with androgen deprivation therapies (ADTs) varies dramatically. Clinical experience has demonstrated difficulties in predicting individual risk for progression due to chemoresistance. Drug combinations that inhibit androgen biosynthesis (e.g., abiraterone acetate) and androgen signaling (e.g., enzalutamide or apalutamide) have proven so effective that new forms of ADT resistance are emerging. In particular, prostate cancers with a neuroendocrine transcriptional signature, which demonstrate greater plasticity, and potentially, increased predisposition to metastasize, are becoming more prevalent. Notably, these subtypes had in fact been relatively rare before the widespread success of novel ADT regimens.Therefore, better understanding of these resistance mechanisms and potential alternative treatments are necessary to improve progression-free survival for patients treated with ADT. Targeting the bromodomain and extra-terminal (BET) protein family, specifically BRD4, with newer investigational agents may represent one such option.Several families of chromatin modifiers appear to be involved in ADT resistance and targeting these pathways could also offer novel approaches. However, the limited transcriptional and genomic information on ADT resistance mechanisms, and a serious lack of patient diversity in clinical trials, demand profiling of a much broader clinical and demographic range of patients, before robust conclusions can be drawn and a clear direction established.

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Histone Demethylase KDM5B as a Therapeutic Target for Cancer Therapy

Cited by 32 publications

References 86 publications

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity

High Risk-Human Papillomavirus in HNSCC: Present and Future Challenges for Epigenetic Therapies

Novel forms of prostate cancer chemoresistance to successful androgen deprivation therapy demand new approaches: Rationale for targeting BET proteins

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