Advances Toward Lsd1 Inhibitors for Cancer Therapy

Fu, Xiaoli; Zhang, Peng; Yu, Bin

doi:10.4155/fmc-2017-0068

Cited by 112 publications

(78 citation statements)

References 64 publications

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“…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.…”

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confidence: 99%

“…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).…”

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confidence: 99%

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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.

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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,...

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confidence: 99%

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confidence: 99%

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.

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“…The histone demethylase LSD1 removes mono- and di-methyl marks from H3K4 and H3K9 and shares structural homology with monoamine oxidases (MAOs) in the brain. It can be targeted by several drug candidates 11 and has been therapeutically exploited in other cancers such as acute myeloid leukemia 12 , sarcoma 13 , and neuroblastoma 14 . LSD1 inhibition has been shown to have an enticing therapeutic window that is selective for cancer cells, in part through its disruption of oncogenic and onco-maintenance transcriptional programs 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in diffuse intrinsic pontine glioma (DIPG)

Bailey

Romero²,

Becher³

et al. 2019

Preprint

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BackgroundDiffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor. Mutations in the H3 histone tail (H3.1/3.3-K27M) are a feature of DIPG, potentially rendering them therapeutically sensitive to small-molecule inhibition of chromatin modifiers. Pharmacological inhibition of lysine specific demethylase-1 (LSD1) shows promise in pediatric cancers such as Ewing’s sarcoma, but has not been investigated in DIPG, which was the aim of our study.MethodsPatient-derived DIPG cell lines and pediatric high-grade glioma (pHGG) datasets were used to evaluate effects of several LSD1 inhibitors on selective cytotoxicity and immune gene expression. Immune cell cytotoxicity was assessed in DIPG cells treated with LSD1 inhibitors and informatics platforms were used to determine immune infiltration of pHGG and impact on survival.ResultsSelective cytotoxicity and an immunogenic gene signature was established in DIPG lines using several clinically-relevant LSD1 inhibitors. Pediatric high-grade glioma patient sequencing data demonstrated survival benefit using this LSD1-dependent gene signature. On-target binding of catalytic LSD1 inhibitors was confirmed in DIPG and pre-treatment of DIPG with these inhibitors increased lysis by natural killer (NK) cells. CIBERSORT analysis of patient data confirmed NK infiltration is beneficial to patient survival while CD8 T-cells are negatively prognostic. Catalytic LSD1 inhibitors are non-perturbing to NK cells while scaffolding LSD1 inhibitors are toxic to NK cells and do not induce the gene signature in DIPG cells.ConclusionsLSD1 inhibition using catalytic inhibitors are both selectively cytotoxic and promote an immune gene signature that is associated with NK cell killing, representing a therapeutic opportunity for pHGG.Key pointsLSD1 inhibition using several clinically relevant compounds is selectively cytotoxic in DIPG.An LSD1-controlled gene signature predicts survival in pediatric high-grade glioma patients.LSD1 inhibition enhances NK cell cytotoxicity against DIPG with correlative genetic biomarkers.Importance of the studyThis is the first study to evaluate inhibition of LSD1 in a uniformly lethal type of pediatric brain tumor: DIPG. We demonstrate selective cytotoxicity of several clinically relevant compounds against patient derived DIPG cells, and identify an immune gene signature that is upregulated in DIPG cells by catalytic inhibitors of LSD1. This immune gene signature is predictive of prognosis in pHGG, consistent with the rationale of promoting this signature through LSD1 inhibition. NK cell killing of DIPG is enhanced by LSD1 inhibition, providing functional confirmation of this gene signature, and represents the first report of LSD1 inhibition promoting NK cell cytotoxicity of cancer cells. Given the poor prognosis of pHGGs and lack of effective treatments, our results suggest use of LSD1 inhibition as a single agent or in combination with NK cell therapy may be a safe and efficacious strategy.

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“…To date, a number of LSD1 inhibitors has been developed . LSD1 inhibitors are mainly categorized into two types, irreversible inhibitors and reversible inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the development of LSD1 selective‐inhibitors is highly desired. Currently, several irreversible LSD1 inhibitors [e. g., ORY‐1001 ( 4 ), GSK2879552 ( 5 ), ORY‐2001, INCB‐059872, IMG‐7289 and CC‐90011] are being tested in clinical trials for cancers and neurodegenerative disorders ,…”

Section: Introductionmentioning

confidence: 99%

Drug Design Concepts for LSD1‐Selective Inhibitors

Ota

Suzuki

2018

The Chemical Record

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Lysine‐specific demethylase 1 (LSD1) is one of the flavin‐dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1‐selective inhibitors using target‐guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1‐selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1‐selective inhibitors.

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Advances Toward Lsd1 Inhibitors for Cancer Therapy

Cited by 112 publications

References 64 publications

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

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

Pharmacologic inhibition of lysine specific demethylase-1 (LSD1) as a therapeutic and immune-sensitization strategy in diffuse intrinsic pontine glioma (DIPG)

Drug Design Concepts for LSD1‐Selective Inhibitors

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