Histone Lysine Demethylase Inhibitors

Jambhekar, Ashwini; Anastas, Jamie N.; Shi, Yang

doi:10.1101/cshperspect.a026484

Cited by 59 publications

(48 citation statements)

References 178 publications

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“…However, these models have technical limitations and improvements with regard to the crossing of the blood-brain barrier (BBB) and the tissue penetrance of Corin, and other related molecules are needed to develop combined LSD1/HDAC inhibition as a therapy. Interestingly, tranylcypromine and phenelzine sulfate, two US Food and Drug Administration-approved drugs that act as monoamine oxidase and non-selective LSD1 inhibitors (Culhane et al, 2010;Jambhekar et al, 2017;Prusevich et al, 2014), cross the BBB and might be combined with HDACi in a drug repurposing strategy. Finally, new generations of LSD1i, such as T-448 (Matsuda et al, 2019), which also crosses the BBB but has minimal hematological toxicity, might also be used systemically to treat DIPG.…”

Section: Discussionmentioning

confidence: 99%

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

et al. 2019

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“…Histone demethylases have emerged as a novel class of epigenetic regulators controlling cancer initiation and progression [ 30 ]. Dysregulated expression and functions of histone lysine demethylases are found in many types of cancers, and thus represent novel promising therapeutic targets for cancer.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of lysine-specific demethylase 2 (LSD2/KDM1B) in breast cancer progression

Chen

Vasilatos

et al. 2017

Oncotarget

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Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line. TCGA- Oncomine database showed that LSD2 expression is significantly higher in basal-like breast tumors compared to other breast cancer subtypes or normal breast tissue. Overexpression of LSD2 in MDA-MB-231 cells significantly altered the expression of key important epigenetic modifiers such as LSD1, HDAC1/2, and DNMT3B; promoted cellular proliferation; and augmented colony formation in soft agar; while attenuating motility and invasion. Conversely, siRNA-mediated depletion of endogenous LSD2 hindered growth of multiple breast cancer cell lines while shRNA-mediated LSD2 depletion augmented motility and invasion. Moreover, LSD2 overexpression in MDA-MB-231 cells facilitated mammosphere formation, enriched the subpopulation of CD49f+/EpCAM- and ALDHhigh, and induced the expression of pluripotent stem cell markers, NANOG and SOX2. In xenograft studies using immune-compromised mice, LSD2-overexpressing MDA-MB-231 cells displayed accelerated tumor growth but significantly fewer lung metastases than controls. Taken together, our findings provide novel insights into the critical and multifaceted roles of LSD2 in the regulation of breast cancer progression and cancer stem cell enrichment.

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“…In contrast to HDACi-based strategies, one study demonstrated that certain KMT2D nonsense mutations are responsive to gentamicin-induced "read through," thus enhancing the expression of KMT2D target genes [138]. In addition to these approaches, new classes of histone-targeting drug compounds, including histone demethylase inhibitors [139], are currently being developed which may prove useful in the reducing the sequela of K CD COM-ADs.…”

Section: Emerging Treatment Strategies For K CD Com-adsmentioning

confidence: 99%

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

et al. 2020

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The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

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Histone Lysine Demethylase Inhibitors

Cited by 59 publications

References 178 publications

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

Functional characterization of lysine-specific demethylase 2 (LSD2/KDM1B) in breast cancer progression

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

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