Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA

Ombra, Maria Neve; Santi, Annalisa Di; Abbondanza, Ciro; Migliaccio, Antimo; Avvedimento, Enrico V.; Perillo, Bruno

doi:10.1016/j.bbagrm.2013.03.003

Cited by 26 publications

(24 citation statements)

References 35 publications

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“…In opposition to PELP1‐mediated activation, KDM1A also interacts with the ERα corepressor CAC1, which binds KDM1A/ERα, reduces occupancy of the complex on target genes, allows H3K9me2 accumulation, and represses gene transcription (Figure b) . Additionally, retinoic acid may interfere with the KDM1A‐mediated E2 response, as it appears to prevent activation of protein kinase A (PKA) and prohibits H3K9 demethylation, although the mechanism is not yet clear …”

Section: Functionally Important Interactions Of Kdm1a and Kdm1b Demetmentioning

confidence: 99%

KDM1 class flavin‐dependent protein lysine demethylases

et al. 2015

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Flavin-dependent, lysine-specific protein demethylases (KDM1s) are a subfamily of amine oxidases that catalyze the selective posttranslational oxidative demethylation of methyllysine side chains within protein and peptide substrates. KDM1s participate in the widespread epigenetic regulation of both normal and disease state transcriptional programs. Their activities are central to various cellular functions, such as hematopoietic and neuronal differentiation, cancer proliferation and metastasis, and viral lytic replication and establishment of latency. Interestingly, KDM1s function as catalytic subunits within complexes with coregulatory molecules that modulate enzymatic activity of the demethylases and coordinate their access to specific substrates at distinct sites within the cell and chromatin. Although several classes of KDM1 -selective small molecule inhibitors have been recently developed, these pan-active site inhibition strategies lack the ability to selectively discriminate between KDM1 activity in specific, and occasionally opposing, functional contexts within these complexes. Here we review the discovery of this class of demethylases, their structures, chemical mechanisms, and specificity. Additionally, we review inhibition of this class of enzymes as well as emerging interactions with coregulatory molecules that regulate demethylase activity in highly specific functional contexts of biological and potential therapeutic importance.

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Section: Functionally Important Interactions Of Kdm1a and Kdm1b Demetmentioning

confidence: 99%

KDM1 class flavin‐dependent protein lysine demethylases

et al. 2015

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“…Currently, more than 70% of breast carcinomas are found to be estrogen receptor positive (ER+) [15], exhibiting the positive proliferative effects as a response to the presence of estrogens [16,17]. Although estrogen exposure is now a widely accepted risk factor in breast cancer development, the mechanisms through which estrogens induce breast carcinogenesis have not been described satisfactorily.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Interactions between 17β-Estradiol and DNA Result in Formation of the Hormone-DNA Complexes

Heger

Guráň

Zítka

et al. 2014

IJERPH

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Beyond the role of 17β-estradiol (E2) in reproduction and during the menstrual cycle, it has been shown to modulate numerous physiological processes such as cell proliferation, apoptosis, inflammation and ion transport in many tissues. The pathways in which estrogens affect an organism have been partially described, although many questions still exist regarding estrogens’ interaction with biomacromolecules. Hence, the present study showed the interaction of four oligonucleotides (17, 20, 24 and/or 38-mer) with E2. The strength of these interactions was evaluated using optical methods, showing that the interaction is influenced by three major factors, namely: oligonucleotide length, E2 concentration and interaction time. In addition, the denaturation phenomenon of DNA revealed that the binding of E2 leads to destabilization of hydrogen bonds between the nitrogenous bases of DNA strands resulting in a decrease of their melting temperatures (Tm). To obtain a more detailed insight into these interactions, MALDI-TOF mass spectrometry was employed. This study revealed that E2 with DNA forms non-covalent physical complexes, observed as the mass shifts for app. 270 Da (Mr of E2) to higher molecular masses. Taken together, our results indicate that E2 can affect biomacromolecules, as circulating oligonucleotides, which can trigger mutations, leading to various unwanted effects.

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“…Both in OP6 cells and on MOE sections, we observe several striking examples of “DNA loops” on the allele associated with the LSD1 compartment, but not on other alleles in the same cell (Fig 5C). Interestingly, the effect of Lsd1 on intergenic looping was also observed for E2-stimulated bcl-2 gene activation (Ombra et al, 2013). Such loops may be a prerequisite for interacting with the compartment or may form as a consequence of this interaction.…”

Section: Resultsmentioning

confidence: 90%

Lysine-specific demethylase-1 (LSD1) is compartmentalized at nuclear chromocenters in early post-mitotic cells of the olfactory sensory neuronal lineage

Kilinc

Savarino

Coleman

et al. 2016

Molecular and Cellular Neuroscience

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Mammalian olfaction depends on the development of specialized olfactory sensory neurons (OSNs) that each express one odorant receptor (OR) protein from a large family of OR genes encoded in the genome. The lysine-specific demethylase-1 (LSD1) protein removes activating H3K4 or silencing H3K9 methylation marks at gene promoters and is required for proper OR regulation. We show that LSD1 protein exhibits variable organization within nuclei of developing OSNs, and tends to consolidate into a single dominant compartment at the edges of chromocenters within nuclei of early post-mitotic cells of the mouse olfactory epithelium (MOE). Using an immortalized cell line derived from developing olfactory placode, we show that consolidation of LSD1 appears to be cell-cycle regulated, with a peak occurrence in early G1. LSD1 co-compartmentalizes with CoREST, a protein known to collaborate with LSD1 to carry out a variety of chromatin-modifying functions. We show that LSD1 compartments co-localize with 1–3 OR loci at the exclusion of most OR genes, and commonly associate with Lhx2, a transcription factor involved in OR regulation. Together, our data suggests that LSD1 is sequestered into a distinct nuclear space that might restrict a histone-modifying function to a narrow developmental time window and/or range of OR gene targets.

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Retinoic acid impairs estrogen signaling in breast cancer cells by interfering with activation of LSD1 via PKA

Cited by 26 publications

References 35 publications

KDM1 class flavin‐dependent protein lysine demethylases

KDM1 class flavin‐dependent protein lysine demethylases

In Vitro Interactions between 17β-Estradiol and DNA Result in Formation of the Hormone-DNA Complexes

Lysine-specific demethylase-1 (LSD1) is compartmentalized at nuclear chromocenters in early post-mitotic cells of the olfactory sensory neuronal lineage

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