A Comprehensive Review of Lysine-Specific Demethylase 1 and its Roles in Cancer

Hosseini, Amir; Minucci, Saverio

doi:10.2217/epi-2017-0022

Cited by 125 publications

(103 citation statements)

References 174 publications

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…As expected mutant mice treated with vehicle showed While TCP is a prototype irreversible LSD1 inhibitor, it also inhibits two major isoforms of monoamine oxidases MAO-A and MAO-B. To control for effects of MAO inhibition on WM we also evaluated the effect of ORY-1001, a TCP-derivative that represents the most potent and selective LSD1 inhibitor described to date (Hosseini and Minucci, 2017;Maes et al, 2015;Maes et al, 2018). The compound has an IC50 of 18 nM and an over 1000-fold selectivity for LSD1 compared to MAOs (Maes et al, 2015;Maes et al, 2018).…”

Section: Setd1a Targets Synaptic Genes With Postnatally-biased Expresmentioning

confidence: 90%

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

Mukai

Cannavò

Sun

et al. 2019

Preprint

View full text Add to dashboard Cite

SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutationof the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.

show abstract

Section: Setd1a Targets Synaptic Genes With Postnatally-biased Expresmentioning

confidence: 90%

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

Mukai

Cannavò

Sun

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…38 LSD1 inhibitors are under clinical investigation for prostate cancer and other cancers. 39 Repressor element 1-silencing transcription (REST) factor…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic modulations and lineage plasticity in advanced prostate cancer

et al. 2020

View full text Add to dashboard Cite

Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

show abstract

“…LSD1 Inhibits the Cellular Functions of FBXW7. LSD1 is overexpressed in multiple human cancers with an oncogenic role and was validated as an attractive cancer target (41). Given that the vast majority of LSD1 functional studies were focused on its enzymatic activity, extensive drug discovery efforts have been made to identify its inhibitors of demethylase activity (9,32,42).…”

Section: Lsd1 Negatively Regulates Fbxw7 Stability Through Both Protementioning

confidence: 99%

“…Given that the vast majority of LSD1 functional studies were focused on its enzymatic activity, extensive drug discovery efforts have been made to identify its inhibitors of demethylase activity (9,32,42). Indeed, some of these inhibitors have been advanced to phase I/ IIa clinical trials (41). Having established a demethylase-independent function of LSD1 in FBXW7 degradation, we next determined its biological consequence with a main focus on the regulation of FBXW7 functions in growth suppression (12), DNA damage repair, and radiation protection (25).…”

Section: Lsd1 Negatively Regulates Fbxw7 Stability Through Both Protementioning

confidence: 99%

“…Our study also has a translational implication. The efforts to discover LSD1 demethylase inhibitors, some of them currently in phase I/IIa clinical trials (41), should be extended to small molecules that specifically bind to LSD1, not necessary to inhibit its demethylase activity, for PROTAC-based degradation (45). This type of LSD1-specific PROTAC drugs that trigger LSD1 degradation should have broad utility for the treatment of human cancers harboring a wild-type FBXW7 with LSD1 overexpression, as well as for immunotherapy in combination with PD-L1 blockade (46).…”

Section: Lsd1 Negatively Regulates Fbxw7 Stability Through Both Protementioning

confidence: 99%

See 1 more Smart Citation

LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity

Lan

Tan

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

FBXW7 acts as a typical tumor suppressor, with loss-of-function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudosubstrate of FBXW7 and LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation, but instead promotes FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome as well as lysosome in a manner dependent on autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, nonhomologous end-joining repair, and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, not only its demethylase activity, might be a unique approach for LSD1-based drug discovery for anticancer application. degradation | DNA damage repair | SCF E3 ligase | ubiquitylation L SD1 (also known as KDM1A) was the first histone demethylase identified as a transcriptional repressor to regulate gene expression via catalyzing the demethylation of mono-and dimethylated histone 3 lysine 4 (H3K4Me1, H3K4Me2) (1). Subsequent studies demonstrated that LSD1 also demethylates H3K9 (Me1 and Me2) to trigger gene activation programs (2). In addition to histone 3, recent studies showed that LSD1 also acts as demethylase of nonhistone proteins, such as p53 (3), E2F1 (4), and HIF-1α (5). Furthermore, LSD1 was shown to cooperate with multiple transcriptional regulators, such as CoREST (2), NuRD (6), and SIRT1/ HDAC (7). Through these activities, LSD1 serves as a master regulator of gene expression and protein function and is actively involved in many biological processes.LSD1 is overexpressed in many human cancers which is associated with poor patient survival (8). Increased preclinical data validated LSD1 as an attractive cancer target, resulting in extensive drug discovery efforts (9). So far, most of LSD1 studies focused on its demethylase activity and associated biological functions. Likewise, all drug discovery efforts on LSD1 targeting were directed to find the demethylase inhibitors (9). However, whether LSD1 has other activities/functions independent of its demethylase activity, and what is the underlying mechanism remain largely unknown, although a recent study showed that ZNF217 naturally interacts with LSD1 to coordinately regulate gene expression independently of its demethylase functions in a prostate cancer model (10).The tumor suppressor FBXW7 functions as a well-characterized substrate recognition subunit of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase (11,12). SCF FBXW7 promotes ubiquitylation and degradation of a large number of oncogenic substrates such as Cyclin E, c-JUN,...

show abstract

A Comprehensive Review of Lysine-Specific Demethylase 1 and its Roles in Cancer

Cited by 125 publications

References 174 publications

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice

Epigenetic modulations and lineage plasticity in advanced prostate cancer

LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity

Contact Info

Product

Resources

About