Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway

Ambrosio, Susanna; Saccà, Carmen D.; Amente, Stefano; Paladino, Simona; Lania, Luigi; Majello, Barbara

doi:10.1038/onc.2017.267

Cited by 79 publications

(78 citation statements)

References 53 publications

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“…LSD1 as an epigenetic regulator of the autophagic pathway is pivotal in protecting oocytes from massive loss. Studies including ours have proved that LSD1 localizes to the nucleus of cells (Kahl et al, ; Lim et al, ) and is critical for the negative regulation of genes essential for the autophagic process by recruiting to the promoters of genes like Atg3 , Atg10 , transcription factor EB ( Tfeb) , sestrin 2 ( Sesn2 ), and p62 (Ambrosio, Ballabio, & Majello, ; Ambrosio & Majello, ; Ambrosio et al, ; Byun et al, ; Periz et al, ; Sardiello et al, ; Settembre et al, ; Wang, Long, et al, ). LSD1 importing to the nucleus is related to its N‐terminal nuclear localization signal motifs (Jin et al, ).…”

Section: Discussionmentioning

confidence: 90%

“…Interestingly, the underlying mechanisms of LSD1‐induced autophagy vary considerably depending on specific circumstances (Ambrosio & Majello, ; Byun et al, ; Wang, Long, et al, ). In neuroblastoma cells, LSD1 represses SESN2 expression, which hampers mTORC1 activity (Ambrosio et al, ). In liver cells, LSD1 mediates fed‐state hormone signaling in preventing autophagy (Byun et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…to the promoters of genes like Atg3, Atg10, transcription factor EB (Tfeb), sestrin 2 (Sesn2), and p62 (Ambrosio, Ballabio, & Majello, 2019;Ambrosio et al, 2017;Byun et al, 2017;Periz et al, 2015;Sardiello et al, 2009;Settembre et al, 2011;Wang, Long, et al, 2017). LSD1 importing to the nucleus is related to its N-terminal nuclear localization signal motifs (Jin et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…However, only a handful of studies have indicated that epigenetic modification plays an important role in controlling oocyte PCD during PF pool establishment (Sun et al, , ). Most recent studies uncovered the potential role of LSD1, in mediating autophagy in various cell types (Ambrosio et al, ; Byun et al, ; Periz et al, ). LSD1 is the first identified lysine‐specific demethylase that specifically marks H3K4me1/2 and/or H3K9me1/2 via a FAD‐dependent oxidative reaction (Shi et al, ).…”

Section: Introductionmentioning

confidence: 99%

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LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

Zhang

Zhu

et al. 2020

Aging Cell

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In female mammals, the size of the initially established primordial follicle (PF) pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the PF pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Although apoptosis and autophagy are involved in the process of oocyte loss, the underlying mechanisms require substantial study. Here, we identify a new role of lysine‐specific demethylase 1 (LSD1) in controlling the fate of oocytes in perinatal mice through regulating the level of autophagy. Our results show that the relatively higher level of LSD1 in fetal ovaries sharply reduces from 18.5 postcoitus (dpc). Meanwhile, the level of autophagy increases while oocytes are initiating programmed death. Specific disruption of LSD1 resulted in significantly increased autophagy and obviously decreased oocyte number compared with the control. Conversely, the oocyte number is remarkably increased by the overexpression of Lsd1 in ovaries. We further demonstrated that LSD1 exerts its role by regulating the transcription of p62 and affecting autophagy level through its H3K4me2 demethylase activity. Finally, in physiological conditions, a decrease in LSD1 level leads to an increased level of autophagy in the oocyte when a large number of oocytes are being lost. Collectively, LSD1 may be one of indispensible epigenetic molecules who protects oocytes against preterm death through repressing the autophagy level in a time‐specific manner. And epigenetic modulation contributes to programmed oocyte death by regulating autophagy in mice.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

Zhang

Zhu

et al. 2020

Aging Cell

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“…LSD1 is an epigenetic enzyme that can either repress target gene expression by demethylating mono-or di-methylated histone H3 lysine 4 (H3K4me1/2) or activate targets by removing repressive H3K9me1/2. LSD1 is implicated in tumorigenesis and progression of many cancers and high LSD1 levels frequently correlate with aggressive cancer features (43)(44)(45). LSD1 also promotes tumor progression through demethylation of non-histone substrates such as p53, E2F1, DNMT1, and MYPT1, a regulator of RB1 phosphorylation (46)(47)(48)(49)(50).…”

Section: Introductionmentioning

confidence: 99%

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

Soldi

Halder

Weston

et al. 2020

Preprint

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Chromatin remodeling SWItch/Sucrose-NonFermentable (SWI/SNF) complexes, initially identified in yeast 20 years ago, are evolutionarily conserved multi-subunit protein complexes that use the energy from hydrolysis of adenosine triphosphate (ATP) to remodel nucleosome structure and modulate transcription. Mutations in proteins of SWI/SNF complexes occur in 20% of human cancers including ovarian cancer (OC). Approximately 50% of ovarian clear cell carcinoma (OCCC) carries mutations in the SWI/SNF subunit ARID1A while small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is driven primarily by genetic inactivation of the SWI/SNF ATPase SMARCA4 (BRG1) alongside epigenetic silencing of the homolog ATPase SMARCA2 (BRM). Dual loss of these ATPases disrupts SWI/SNF chromatin remodeling activity and may alsointerfere with the function of other histone-modifying enzymes that associate with or are dependent on SWI/SNF activity. One such enzyme is lysine-specific histone demethylase 1 (LSD1/KDM1A) which regulates the chromatin landscape and gene expression by demethylating proteins, including histone H3. LSD1 associates with epigenetic complexes such as the nucleosome remodeling deacetylase complex (NuRD) and SWI/SNF to inhibit the transcription of genes involved in tumor suppression and cell differentiation. TGCA analysis of human cancers shows that LSD1 is highly expressed in SWI/SNF-mutated tumors. Further, SCCOHT and OCCC cell lines show low nM IC 50 s for the reversible LSD1 inhibitor SP-2577 (Seclidemstat, currently in clinical phase I trials), supporting that these SWI/SNF-deficient ovarian cancers are dependent on LSD1 activity. Recently, it has been also shown that inhibition of LSD1 stimulates interferon (IFN)-dependent anti-tumor immunity through induction of Endogenous Retroviruses Elements (ERVs) and may thereby overcome resistance to checkpoint blockade. Additionally, SCCOHTs have been shown to exhibit an immune-active tumor microenvironment with PD-L1 expression in both tumor and stromal cells that strongly correlated with T cell infiltration. Thus, in this study we investigated the ability of SP-2577 to promote anti-tumor immunity and T cell infiltration in SWI/SNF-mutant SCCOHT and OCCC models. Our data shows that the reversible LSD1 inhibitor SP-2577 stimulates IFN-dependent anti-tumor immunity in SCCOHT cells in vitro in a 3D immuneorganoid platform. Additionally, SP-2577 promoted the expression of PD-L1 in both SCCOHT and OCCC models. Together our findings suggest that SP-2577 and checkpoint inhibitors as a therapeutic combination may induce or augment immunogenic responses in these tumors.

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The Role of Dynamic Epigenetic Changes in Modulating Homeostasis after Exposure to Low‐dose Environmental Chemicals

Yuan¹,

Freeman²,

Xie³

et al. 2022

Genomic and Epigenomic Biomarkers of Toxicology and Disease

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Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway

Cited by 79 publications

References 53 publications

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer

The Role of Dynamic Epigenetic Changes in Modulating Homeostasis after Exposure to Low‐dose Environmental Chemicals

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