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LSD1 maintains mammary luminal cell differentiation and suppresses luminal breast cancer cell invasion

ABSTRACT: LSD1 (KDM1A) is a histone demethylase that plays both oncogenic and tumor suppressor roles in breast cancer. However, the exact contexts under which it plays these opposite roles remain largely elusive. By characterizing its role in normal and cancerous luminal mammary epithelial cells (MECs), here we show that LSD1 is essential for maintaining differentiation and survival of luminal cells. LSD1-inhibition by both genetic and pharmacological approaches increases invasion of luminal breast cancer cells. Mechanistically, we find LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. LSD1 positively regulates GATA3 expression and represses that of TRIM37, a histone H2A ubiquitin ligase and breast cancer oncoprotein. LSD1-loss leads to reduced expression of several cell junction genes (e.g., CDH1, VCL, CTNNA1), possibly via TRIM37-mediated repression. Collectively, our data suggest LSD1 largely plays a tumor suppressor role in luminal breast cancer and the increased MEC invasiveness associated with LSD1-inhibition can be blocked via TRIM37-inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95165 | GEO | 2019/08/16

REPOSITORIES: GEO

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The¬¬¬ androgen receptor interacts with GATA3 to transcriptionally regulate a luminal epithelial cell phenotype in breast cancer

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2024-01-30 | PXD047997 | Pride

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Cancer-associated E239K mutation of LSD1 promotes the migration and invasion of luminal breast cancer cells by reducing the expression of ERα

Project description:Background: Epithelial to mesenchymal transition (EMT) plays an essential role in the metastasis of breast cancer by regulating the migration and invasion of cancer cells. Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates EMT. However, the functional effects of the mutation on LSD1 in breast cancer remain unclear. Results: An E239K mutation of LSD1 was identified from TCGA Breast Invasive Carcinoma cohort. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with the wild-type LSD1, but not the E239K mutated LSD1, suppressed the increased invasion of the LSD1 knockdown cells, demonstrating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion of breast cancer cells. Further analysis showed that the E239K mutation of LSD1 led to decreased expression of estrogen receptor α (ERα), which subsequently increased the expression of Slug, a master transcription factor that promoted EMT. Most importantly, the E239K mutation of LSD1 disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of ERα gene. The reduced enrichment of LSD1 at the promoter region of ERα gene caused enhanced histone H3K9 methylation, which in turn suppressed the transcription of ERα gene. Conclusions: The E239K mutation of LSD1 promotes the migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3, which reduces the expression of ERα by enhancing the histone H3K9 methylation.

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GATA3 Reprograms Basal Breast Cancer Cells towards a Luminal Subtype and Inhibits Metastases through Suppression of Lysyl Oxidase

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AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-negative cell line RNA-seq]

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AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive cell line RNA-seq]

2023-12-21 | GSE176005 | GEO

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