Pharmacological inhibition of KDM5A for cancer treatment

Yang, Guan–Jun; Wu, Jia; Liang, Miao; Zhu, Minghui; Zhou, Qianjin; Lu, Xin-Jiang; Lu, Jian-Fei; Leung, Chung‐Hang; Ma, Dik‐Lung; Chen, Jiong

doi:10.1016/j.ejmech.2021.113855

Cited by 26 publications

(34 citation statements)

References 165 publications

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“…The growing interest in KDM5A as a cancer driver has spurred efforts to develop specific small‐molecule inhibitors for this factor (summarized in Figure 5B). [ 48 ] The majority of inhibitors developed thus far work through blocking the activity of the KDM5A JmjC domain, a domain that iteratively demethylates H3K4me3 through a two‐step reaction mechanism. The first step requires 2‐oxoglutarate (2OG), oxygen (O 2 ), and Fe(II), to form a hydroxymethyl intermediate, which also generates carbon dioxide (CO 2 ) and succinate as byproducts (Figure 5A).…”

Section: Therapeutic Targeting Of Kdm5a With Parp Inhibitors?mentioning

confidence: 99%

“…Considering the reported prevalence of KDM5A-dependent proliferation in several cancers [43,46,48] , the identification of PARP1 and macroH2A1.2 as upstream regulators of KDM5A present potentially new and exciting opportunities for therapeutic intervention. Foremost, the dependency of KDM5A on PARP1 indicates that cancers driven by KDM5A overexpression [46] may be selectively treated with FDA approved PARPi.…”

Section: Therapeutic Targeting Of Kdm5a With Parp Inhibitors?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…[43] Recently, KDM5A has gained attention for its role in promoting the progression of specific cancer types, including breast, [44] osteosarcoma, [43] and lung cancers, [42,45] all of which present with significantly elevated levels of KDM5A. [46][47][48] Additional cancers have been identified with KDM5A mutations and importantly, silencing of KDM5A expression can reduce tumor progression in some cancer-contexts (Figure 1B). [41,49] These observations have established KDM5A as an attractive therapeutic target in cancer, which has driven drug development efforts toward identifying specific KDM inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…[41,49] These observations have established KDM5A as an attractive therapeutic target in cancer, which has driven drug development efforts toward identifying specific KDM inhibitors. [48] Given the multifunctionality of KDM5A, it remains unclear how its activities in different biological pathways are related and whether these functions contribute uniquely or collectively to human diseases where KDM5A pathways are found to be dysregulated. Here, we examine recent advances in our understanding of how KDM5A is regulated during the DDR, with a focus on a newly defined PARP1 and macroH2A pathway.…”

Section: Introductionmentioning

confidence: 99%

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Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

2022

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The lysine demethylase KDM5A collaborates with PARP1 and the histone variant macroH2A1.2 to modulate chromatin to promote DNA repair. Indeed, KDM5A engages poly(ADP-ribose) (PAR) chains at damage sites through a previously uncharacterized coiled-coil domain, a novel binding mode for PAR interactions. While KDM5A is a well-known transcriptional regulator, its function in DNA repair is only now emerging.Here we review the molecular mechanisms that regulate this PARP1-macroH2A1.2-KDM5A axis in DNA damage and consider the potential involvement of this pathway in transcription regulation and cancer. Using KDM5A as an example, we discuss how multifunctional chromatin proteins transition between several DNA-based processes, which must be coordinated to protect the integrity of the genome and epigenome. The dysregulation of chromatin and loss of genome integrity that is prevalent in human diseases including cancer may be related and could provide opportunities to target multitasking proteins with these pathways as therapeutic strategies.

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Section: Therapeutic Targeting Of Kdm5a With Parp Inhibitors?mentioning

confidence: 99%

Section: Therapeutic Targeting Of Kdm5a With Parp Inhibitors?mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

2022

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The role and prospect of lysine‐specific demethylases in cancer chemoresistance

Song

Yang

et al. 2023

Medicinal Research Reviews

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Histone methylation plays a key function in modulating gene expression, and preserving genome integrity and epigenetic inheritance. However, aberrations of histone methylation are commonly observed in human diseases, especially cancer. Lysine methylation mediated by histone methyltransferases can be reversed by lysine demethylases (KDMs), which remove methyl marks from histone lysine residues. Currently, drug resistance is a main impediment for cancer therapy. KDMs have been found to mediate drug tolerance of many cancers via altering the metabolic profile of cancer cells, upregulating the ratio of cancer stem cells and drug‐tolerant genes, and promoting the epithelial‐mesenchymal transition and metastatic ability. Moreover, different cancers show distinct oncogenic addictions for KDMs. The abnormal activation or overexpression of KDMs can alter gene expression signatures to enhance cell survival and drug resistance in cancer cells. In this review, we describe the structural features and functions of KDMs, the KDMs preferences of different cancers, and the mechanisms of drug resistance resulting from KDMs. We then survey KDM inhibitors that have been used for combating drug resistance in cancer, and discuss the opportunities and challenges of KDMs as therapeutic targets for cancer drug resistance.

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Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway

Liu

Zheng

et al. 2022

Cell. Mol. Life Sci.

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The study aimed to investigate the potential role of lysine-specific demethylase 5A (KDM5A) in cisplatin-induced ototoxicity. The effect of the KDM5A inhibitor CPI-455 was assessed by apoptosis assay, immunofluorescence, flow cytometry, seahorse respirometry assay, and auditory brainstem response test. RNA sequencing, qRT-PCR, and CUT&Tag assays were used to explore the mechanism underlying CPI-455-induced protection. Our results demonstrated that the expression of KDM5A was increased in cisplatin-injured cochlear hair cells compared with controls. CPI-455 treatment markedly declined KDM5A and elevated H3K4 trimethylation levels in cisplatin-injured cochlear hair cells. Moreover, CPI-455 effectively prevented the death of hair cells and spiral ganglion neurons and increased the number of ribbon synapses in a cisplatin-induced ototoxicity mouse model both in vitro and in vivo. In HEI-OC1 cells, KDM5A knockdown reduced reactive oxygen species accumulation and improved mitochondrial membrane potential and oxidative phosphorylation under cisplatin-induced stress. Mechanistically, through transcriptomics and epigenomics analyses, a set of apoptosis-related genes, including Sos1, Sos2, and Map3k3, were regulated by CPI-455. Altogether, our findings indicate that inhibition of KDM5A may represent an effective epigenetic therapeutic target for preventing cisplatin-induced hearing loss.

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Pharmacological inhibition of KDM5A for cancer treatment

Cited by 26 publications

References 165 publications

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?)

The role and prospect of lysine‐specific demethylases in cancer chemoresistance

Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway

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