Histone Demethylases in Cancer

Sainathan, Satheesh K.; Paul, Santanu; Ramalingam, Satish; Baranda, Joaquina; Anant, Shrikant; Dhar, Animesh

doi:10.1007/s40495-015-0025-y

Cited by 11 publications

(3 citation statements)

References 129 publications

(145 reference statements)

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“…Lysine methyltransferases and demethylases have been reported to be able to catalyze the process of N -methylation and N -demethylation of histone lysines, respectively [1, 2]. Based on the catalytic mechanisms, the demethylases are divided into two subgroups: the flavin adenine dinucleotide (FAD)-dependent LSD1 and LSD2 and JMJD family containing JmjC domain [3]. Prior to the discovery of the first demethylase LSD1 (also named KDM1A, KIAA0601, BHC110, and AOF2) in 2004 [4], the process of histone methylation is considered to be irreversible.…”

Section: Introductionmentioning

confidence: 99%

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

2019

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Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.

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Section: Introductionmentioning

confidence: 99%

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

2019

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“…13 Many cancers overexpress members of the Jmjd2 family of KDMs. 14 Their inhibition suppresses the growth of tumor cells, suggesting the therapeutic implications of targeting these proteins. 12,15,16 KDM3A (lysine demethylase 3A or JMJD1A or JHDM2A) is involved in regulating gene expression in numerous biological processes by demethylating mono-or di-methylated H3K9.…”

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confidence: 99%

The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice

et al. 2019

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BACKGROUND & AIMS: The histone lysine demethylase 3A (KDM3A) demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells. METHODS: We knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (human noncancerous pancreatic ductal cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-sequencing analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 messenger RNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time. RESULTS: Levels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent nontumor pancreatic tissues, such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 messenger RNA were higher in human PDAC than nontumor pancreatic tissues and correlated with shorter survival times of patients. CONCLUSIONS: We found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in pancreatic cancer cell lines reduced their invasive and sphereforming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.

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“…The loss of KDM3B disrupts an epigenetic program by inhibiting p53-p21 signaling, and enhancing cancer cell development and survival [ 87 ]. Histone demethylases may not always overexpress; in fact, they may even be downregulated in some malignancies [ 88 , 89 , 90 , 91 ]. However, this depends more on the lysine/arginine residues of oncogene and tumor suppressor genes ( Figure 2 ).…”

Section: Histone Demethylase Dysregulation and Cancermentioning

confidence: 99%

Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression

Srivastava

Singh²,

Jauhari

et al. 2023

Epigenomes

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Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.

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Histone Demethylases in Cancer

Cited by 11 publications

References 129 publications

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

LSD1/KDM1A inhibitors in clinical trials: advances and prospects

The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors, Regulates Expression of DCLK1 and Promotes Tumorigenesis in Mice

Histone Demethylase Modulation: Epigenetic Strategy to Combat Cancer Progression

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