MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

Luo, Huacheng; Shenoy, Anitha; Li, Xuehui; Jin, Yue; Jin, Ling; Cai, Qingsong; Tang, Ming; Liu, Yang; Chen, Hao; Reisman, David; Wu, Lizi; Seto, Edward; Qiu, Yi; Dou, Yali; Casero, Robert A.; Lu, Jinhua

doi:10.1016/j.celrep.2016.05.050

Cited by 70 publications

(77 citation statements)

References 68 publications

(107 reference statements)

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“…It is possible that KDAC activity may regulate LSD1 activity through deacetylation of core complex subunits or of proteins that can associate with the complex in a regulated fashion. Avery recent study shows that acetylation of LSD1 disrupts its ability to interact with nucleosomes in vitro and cellular chromatin [59]. However, we do not observe a decrease in LSD1 association with promoter chromatin upon KDAC inhibition.…”

Section: Discussioncontrasting

confidence: 92%

Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

Patrick

Griggs

Icenogle

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Small molecule inhibitors of lysine deacetylases (KDACs) are approved for clinical use in treatment of several diseases. Nuclear receptors, such as the glucocorticoid receptor (GR) use lysine acetyltransferases (KATs or HATs) and KDACs to regulate transcription through acetylation and deacetylation of protein targets such as histones. Previously we have shown that KDAC1 activity facilitates GR-activated transcription at about half of all cellular target genes. In the current study we examine the role of Class I KDACs in glucocorticoid-mediated repression of gene expression. Inhibition of KDACs through two structurally distinct Class I-selective inhibitors prevented dexamethasone (Dex)-mediated transcriptional repression in a gene-selective fashion. In addition, KDAC activity is also necessary to maintain repression. Steroid receptor coactivator 2 (SRC2), which is known to play a vital role in GR-mediated repression of pro-inflammatory genes, was found to be dispensable for repression of glucocorticoid target genes sensitive to KDAC inhibition. At the promoters of these genes, KDAC inhibition did not result in altered nucleosome occupancy or histone H3 acetylation. Surprisingly, KDAC inhibition rapidly induced a significant decrease in H3K4Me2 at promoter nucleosomes with no corresponding change in H3K4Me3, suggesting the activation of the lysine demethylase, LSD1/KDM1A. Depletion of LSD1 expression via siRNA restored Dex-mediated repression in the presence of KDAC inhibitors, suggesting that LSD1 activation at these gene promoters is incompatible with transcriptional repression. Treatment with KDAC inhibitors does not alter cellular levels of LSD1 or its association with Dex-repressed gene promoters. Therefore, we conclude that Class I KDACs facilitate Dex-induced transcriptional repression by suppressing LSD1 complex activity at selected target gene promoters. Rather than facilitating repression of transcription, LSD1 opposes it in these gene contexts.

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Section: Discussioncontrasting

confidence: 92%

Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

Patrick

Griggs

Icenogle

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…33 MOF (male absent on the first) acetyltransferase was responsible for acetylation of LSD1 in epithelial cells, whereas acetylation was not observed in mesenchymal cells. The lack of acetylation in mesenchymal cells could be partly due to the overexpression of HDAC1.…”

Section: Resultsmentioning

confidence: 97%

“…Instead, acetylation-dependent LSD1 activity might require nucleosomal substrate rather than peptide substrate, which is consistent with prior work. 5,33 Given the requirement of full length H3 protein, all subsequent experiments were conducting in cells.…”

Section: Resultsmentioning

confidence: 99%

LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation

Nalawansha

Pflum

2016

ACS Chem. Biol.

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Lysine Specific Demethylase 1 (LSD1) catalyzes the demethylation of histone 3 to regulate gene expression. With a fundamental role in gene regulation, LSD1 is involved in multiple cellular processes, including embryonic development, cell proliferation, and metastasis. Significantly, LSD1 is overexpressed in multiple cancers and has emerged as a potential anticancer drug target. LSD1 is typically found in association with another epigenetic enzyme, histone deacetylase (HDAC). HDAC and LSD1 inhibitor compounds have been tested as combination anticancer agents. However, the functional link between LSD1 and HDAC has yet to be understood in detail. Here, we used a substrate trapping strategy to identify cellular substrates of HDAC1. Using inactive HDAC1 mutants, we identified LSD1 as an HDAC1 substrate. HDAC1 mediated deacetylation of LSD1 at K374 in the substrate binding lobe, which affected the histone 3 binding and gene expression activity of LSD1. The mechanistic link between HDAC1 and LSD1 established here suggests that HDAC inhibitors influence LSD1 activity, which will ultimately guide drug design targeting epigenetic enzymes.

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“…In addition, PLU-1 has been reported to promote drug resistance in melanomas (26) and to drive metastasis and EMT in hepatocellular cancer cells (27), while LSD1 has been shown to promote invasion and metastasis through facilitating EMT in many cancer cell types (28–30). These studies provided a further rationale for the investigation of whether PLU-1 and/or LSD1 play a role in hypoxia induced gefitinib resistance in HCC827 cells.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

Lü

Liu

Oeck

et al. 2018

Molecular Cancer Research

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The development of small-molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional therapy. This study, documents that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation. Following hypoxic growth conditions, HCC827 cells treated with gefitinib upregulated N- cadherin, Fibronectin and Vimentin expression and downregulated E-cadherin, characteristic of an epithelial-mesenchymal transition (EMT) which prior studies have linked to EGFR TKI resistance. Mechanistically, knockdown of the histone demethylases, LSD1 and PLU-1, prevented and reversed hypoxia-induced gefitinib resistance, with inhibition of the associated EMT, suggesting that LSD1 and PLU-1 play key roles in hypoxia-induced gefitinib resistance and EMT. Moreover, hypoxia-treated HCC827 cells demonstrated more aggressive tumor growth in vivo compared to cells grown in normoxia, but inhibition of LSD1 function by shRNA- mediated knockdown or by the small-molecular inhibitor, SP2509, suppressed tumor growth and enhanced gefitinib response in vivo. These results suggest that hypoxia is a driving force for acquired resistance to EGFR TKIs through epigenetic change and coordination of EMT in NSCLC. This study suggests that combination of therapy with EGFR TKIs and LSD1 inhibitors may offer an attractive therapeutic strategy for NSCLCs.

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MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

Cited by 70 publications

References 68 publications

Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

Class I lysine deacetylases promote glucocorticoid-induced transcriptional repression through functional interaction with LSD1

LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation

Hypoxia Promotes Resistance to EGFR Inhibition in NSCLC Cells via the Histone Demethylases, LSD1 and PLU-1

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