The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update

Malagraba, Gianluca; Yarmohammadi, Mahdieh; Javed, Aadil; Barceló, Carles; Rubio-Tomás, Teresa

doi:10.3390/biom12030462

Cited by 20 publications

(12 citation statements)

References 109 publications

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“…In human cells, overexpression of LSD1 is involved in the proliferation, inhibition of apoptosis, and metastasis of several types of cancers, such as gastric, breast, and prostate cancers [ 109 , 118 , 119 ]. The elevated levels of Lsd1/2 proteins at 37°C suggest that their functions might be essential for cell survival at stressful high temperatures.…”

Section: Resultsmentioning

confidence: 99%

The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe

Liu,

Marayati,

de la Cerda

et al. 2024

PLoS Genet

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Eukaryotic chromatin is organized into either silenced heterochromatin or relaxed euchromatin regions, which controls the accessibility of transcriptional machinery and thus regulates gene expression. In fission yeast, Schizosaccharomyces pombe, Set1 is the sole H3K4 methyltransferase and is mainly enriched at the promoters of actively transcribed genes. In contrast, Clr4 methyltransferase initiates H3K9 methylation, which has long been regarded as a hallmark of heterochromatic silencing. Lsd1 and Lsd2 are two highly conserved H3K4 and H3K9 demethylases. As these histone-modifying enzymes perform critical roles in maintaining histone methylation patterns and, consequently, gene expression profiles, cross-regulations among these enzymes are part of the complex regulatory networks. Thus, elucidating the mechanisms that govern their signaling and mutual regulations remains crucial. Here, we demonstrated that C-terminal truncation mutants, lsd1-ΔHMG and lsd2-ΔC, do not compromise the integrity of the Lsd1/2 complex but impair their chromatin-binding capacity at the promoter region of target genomic loci. We identified protein-protein interactions between Lsd1/2 and Raf2 or Swd2, which are the subunits of the Clr4 complex (CLRC) and Set1-associated complex (COMPASS), respectively. We showed that Clr4 and Set1 modulate the protein levels of Lsd1 and Lsd2 in opposite ways through the ubiquitin-proteasome-dependent pathway. During heat stress, the protein levels of Lsd1 and Lsd2 are upregulated in a Set1-dependent manner. The increase in protein levels is crucial for differential gene expression under stress conditions. Together, our results support a cross-regulatory model by which Set1 and Clr4 methyltransferases control the protein levels of Lsd1/2 demethylases to shape the dynamic chromatin landscape.

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Section: Resultsmentioning

confidence: 99%

The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe

Liu,

Marayati,

de la Cerda

et al. 2024

PLoS Genet

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“…In a comprehensive study focusing on liver cancer, HCC (Hepatocellular Carcinoma) cell lines were found to exhibit elevated levels of LSD2. Bayo et al employed various methodologies to identify potential therapeutic targets associated with epigenetic alterations in these cancer cells [30,31]. Previously, it was reported that patients with high tumor expression levels of EZH-2, EHMT2/G9a, KDM3A, KDM4B, and LSD1/KDM1A had significantly worse prognoses [30].…”

Section: Liver Cancer Cellsmentioning

confidence: 99%

LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond

Kim,

Liu

2024

Biomolecules

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Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2’s implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.

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“…During inflammation, LSD1 can act as both a pro-inflammatory and anti-inflammatory epigenetic regulator [ 42 ]. LSD1 can have pro-inflammatory effects, and upregulation can contribute to rheumatoid arthritis, sepsis, hepatitis B virus-associated glomerulonephritis (HBV-GN) and SARS-CoV-2 infection, as well as tumor progression [ 157 ]. It needs to be clarified which of these effects are mediated by MR, as LSD1 acts as coregulator for several NRs.…”

Section: Mr Signaling and Micromilieumentioning

confidence: 99%

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

Griesler

Schuelke

Uhlig

et al. 2022

IJMS

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The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases.

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The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update

Cited by 20 publications

References 109 publications

The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe

The Cross-Regulation Between Set1, Clr4, and Lsd1/2 in Schizosaccharomyces pombe

LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

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