Pharmacological Inhibition of LSD1 for Cancer Treatment

Yang, Guan–Jun; Lei, Pui-Man; Wong, Suk-Yu; Ma, Dik‐Lung; Leung, Chung‐Hang

doi:10.3390/molecules23123194

Cited by 100 publications

(80 citation statements)

References 151 publications

(217 reference statements)

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“…The second lobe forms the substrate binding sub-domain, which is larger in LSD1 than in other amine oxidases, allowing for the recognition and accommodation of the target methylated lysine as well as its neighboring residues [23]. In space, this second lobe is placed adjacently to the SWIRM domain forming a hydrophobic binding pocket that allows for further interactions with the substrates [23] and offers a structural base for the design of LSD1 inhibitors [25,26] The central Tower domain, which is not found in any other monoamine oxidases, is composed of two anti-parallel helices and it protrudes from the AO domain, serving as a docking site for LSD1's interacting protein partners.…”

Section: Lsd1 a Brief Overviewmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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A new exciting area in cancer research is the study of cancer stem cells (CSCs) and the translational implications for putative epigenetic therapies targeted against them. Accumulating evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular reprogramming and, particularly, reversing cancer stemness characteristics, such as self-renewal and chemoresistance. Lysine specific demethylase 1 (LSD1/KDM1A) plays a well-established role in the normal hematopoietic and neuronal stem cells. Overexpression of LSD1 has been documented in a variety of cancers, where the enzyme is, usually, associated with the more aggressive types of the disease. Interestingly, recent studies have implicated LSD1 in the regulation of the pool of CSCs in different leukemias and solid tumors. However, the precise mechanisms that LSD1 uses to mediate its effects on cancer stemness are largely unknown. Herein, we review the literature on LSD1’s role in normal and cancer stem cells, highlighting the analogies of its mode of action in the two biological settings. Given its potential as a pharmacological target, we, also, discuss current advances in the design of novel therapeutic regimes in cancer that incorporate LSD1 inhibitors, as well as their future perspectives.

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Section: Lsd1 a Brief Overviewmentioning

confidence: 99%

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Karakaidos

Verigos

Magklara

2019

Cancers

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“…Lysine-specific histone demethylase 1 (LSD1/KDM1A) is one of the flavin-dependent monoamine oxidoreductase which removes methyl groups from histones H3K4me1/2 and H3K9me1/2 (Yang et al, 2018). LSD1 is aberrantly overexpressed in many cancers, such as neuroblastoma, bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers (Bennani-Baiti et al, 2012) and is therefore an attractive molecular target for anti-neoplastic treatment options (Ota & Suzuki, 2018;Yang et al, 2018). An example of an epigenetic dual inhibitor was recently described by Kalin et al (Kalin et al, 2018).…”

Section: Hdac Inhibitors Plus Lsd1 Inhibitorsmentioning

confidence: 99%

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

Oing

Skowron²,

Bokemeyer

et al. 2019

Andrology

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Background: Type II germ cell tumors represent the most common solid malignancy in men aged 15-45 years. Despite high cure rates of >90% over all stages, 10-15% of advanced patients develop treatment resistance and potentially succumb to their disease. Treatment of refractory germ cell tumors remains unsatisfactory, and new approaches are needed to further improve outcomes. Objectives: With this narrative review, we highlight epigenetic mechanisms related to resistance to standard systemic treatment, which may act as promising targets for novel combined epigenetic treatment approaches. Materials and methods: A comprehensive literature search of PubMed and MEDLINE was conducted to identify original and review articles on resistance mechanisms and/or epigenetic treatment of germ cell tumors in vitro and in vivo. Review articles were hand-searched to identify additional articles. Results: Distinct epigenetic phenomena have been linked to chemotherapy resistance in germ cell tumors, among which DNA hypermethylation, histone acetylation, and bromodomain proteins appear as promising targets for therapeutic exploitation. Inhibitors of key regulators, for example DNA methyltransferases (e.g. decitabine, guadecitabine), histone deacetylases (e.g. romidepsin), and bromodomain proteins (e.g. JQ1) decreased cell viability, triggered apoptosis, and growth arrest. Additionally, these epigenetic drugs induced differentiation and led to loss of pluripotency and re-sensitization towards cisplatin in cell lines and animal models. Discussion: Epigenetic treatments hold promise to (i) reduce the treatment burden of and (ii) overcome resistance to standard cisplatin-based chemotherapy. Combined approaches may enhance activity, while the ideal target and treatment combination of epigenetic drugs, either with another epigenetic agent or conventional cytotoxic agents need to be defined. Conclusion: Epigenetic (combination) treatment for germ cell tumors should be further explored in pre-clinical and clinical research for its potential to further improve germ cell tumor treatment.

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“…Transcription factors and chromatin modifiers play primary roles in the programming 91 and reprogramming of cellular states during development and differentiation, as well as in 92 maintaining the correct cellular transcriptional profile [7]. Indeed, a plethora of groundbreaking 93 studies has demonstrated the importance of posttranslational modifications of histones for 94 transcription control and normal cell development.…”

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confidence: 99%

“…Indeed, a plethora of groundbreaking 93 studies has demonstrated the importance of posttranslational modifications of histones for 94 transcription control and normal cell development. Therefore, the deregulation of epigenetic 95 control is a common feature of a number of diseases, including cancer [7]. 96…”

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confidence: 99%

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Carneiro

Silva

Amaral

et al. 2019

Preprint

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Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ), and due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935. We synthesized a novel and potent LSD1 inhibitor, MC3935, which was used to treat schistosomula or adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.Author SummarySchistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminth Schistosoma mansoni. The control and treatment of the disease rely almost exclusively on praziquantel (PZQ). Thus, there is an urgent need to search for promising protein targets to develop new drugs. Drugs that inhibit enzymes that modify the chromatin structure have been developed for a number of diseases. We and others have shown that S. mansoni epigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of the S. mansoni histone demethylase LSD1 (SmLSD1) as a drug target. We reported the synthesis of a novel and potent LSD1 inhibitor, MC3935, and show that it selectively inhibited the enzymatic activity of SmLSD1. Treatment of juvenile or adult worms with MC3935 caused severe damage to the tegument of the parasites and compromised egg production. Importantly, MC3935 proved to be highly toxic to S. mansoni, culminating in the death of juvenile or adult worms within 96 h. Transcriptomic analysis of MC3935-treated parasites revealed changes in the gene expression of hundreds of genes involved in key biological processes. Importantly, SmLSD1 contains unique sequences within its polypeptide chain that could be explored to develop a S. mansoni selective drug.

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Pharmacological Inhibition of LSD1 for Cancer Treatment

Cited by 100 publications

References 151 publications

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

Epigenetic treatment combinations to effectively target cisplatin‐resistant germ cell tumors: past, present, and future considerations

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

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