The growing structural and functional complexity of the LSD1/KDM1A histone demethylase

Marabelli, C.; Marrocco, Biagina; Mattevi, Andrea

doi:10.1016/j.sbi.2016.07.011

Cited by 31 publications

(26 citation statements)

References 71 publications

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“…These findings underscore the biological importance of LSD1 and therapeutic potential of LSD1 inhibitors for cancer therapy. (Figure 2A) [25,26,27]. To date, over 30 crystal structures of LSD1 have been deposited in RCSB Protein Data Bank with the highest resolution of 2.8 Å (PDB code: 5L3E) [28].…”

Section: Biological Roles Of Lsd1mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

112

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LSD1 has become an important biologically validated epigenetic target for cancer therapy since its identification in 2004. LSD1 mediates many cellular signaling pathways and is involved in the initiation and development of cancers. Aberrant overexpression of LSD1 has been observed in different types of cancers, and inactivation by small molecules suppresses cancer cell differentiation, proliferation, invasion and migration. To date, a large number of LSD1 inhibitors have been reported, RG6016, GSK-2879552, INCB059872, IMG-7289 and CC-90011 are currently undergoing clinical assessment for the treatment of acute myeloid leukemia, small-cell lung cancer, etc. In this review, we briefly highlight recent advances of LSD1 inhibitors mainly covering the literatures from 2015 to 2017 and tentatively propose our perspectives on the design of new LSD1 inhibitors for cancer therapy.

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Section: Biological Roles Of Lsd1mentioning

confidence: 99%

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Zhang

2017

Future Med. Chem.

112

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“…Much of our current understanding of the enzymatic properties of HDAC1 and LSD1 has come from studying these enzymes as purified proteins or in multi-protein complexes besides that of the purified core CoREST complex LSD1/HDAC1/CoREST1 (LHC) ( Hayward and Cole, 2016 ; López et al, 2016 ; Marabelli et al, 2016 ; Millard et al, 2013 ; 2017 ; Wagner et al, 2016 ; Watson et al, 2016 ). Until recently, it has been challenging to make purified, active LHC although an effective method for this has recently been described ( Kalin et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

Hayward

Kalin

et al. 2018

eLife

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The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

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“…Furthermore, KDM1A contains a TOWER domain (90-residue insert), dividing the AOL domain into two subdomains (Fig. 2 ) [ 25 , 26 ]. One subdomain of AOL interacts with the SWIRM domain, forming a core structure that binds FAD, while the other specifically binds the substrate [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…KDM1A regulates the expression of target genes through histone demethylation. In addition to other molecules, KDM1A interacts with several RNAs, including microRNAs such as miR-137 [ 25 ]. miR-137 is expressed in the nervous system and is significant for regulation of neural stem cell differentiation [ 58 ].…”

Section: Introductionmentioning

confidence: 99%

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

Ismail

Lee

Kim

et al. 2018

Epigenetics & Chromatin

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The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more effective anticancer drugs.

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The growing structural and functional complexity of the LSD1/KDM1A histone demethylase

Cited by 31 publications

References 71 publications

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Advances Toward Lsd1 Inhibitors for Cancer Therapy

Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

KDM1A microenvironment, its oncogenic potential, and therapeutic significance

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