Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology

Abstract

Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Since epigenetic changes like histone modifications are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding novel therapies as well as more refined diagnostic and prognostic tools in breast cancer. Lysine-specific demethylase 1 (LSD1) plays a key role in the regulation of gene expression by removing the methyl groups from methylated lysine 4 of histone H3 and lysine 9 of histone H3. LSD1 is essential for mammalian development and involved in many biological processes. Considering recent evidence that LSD1 is involved in carcinogenesis, we investigated the role of LSD1 in breast cancer. Therefore, we developed an enzyme-linked immunosorbent assay to determine LSD1 protein levels in tissue specimens of breast cancer and measured very high LSD1 levels in estrogen receptor (ER)-negative tumors. Pharmacological LSD1 inhibition resulted in growth inhibition of breast cancer cells. Knockdown of LSD1 using small interfering RNA approach induced regulation of several proliferation-associated genes like p21, ERBB2 and CCNA2. Additionally, we found that LSD1 is recruited to the promoters of these genes. In summary, our data indicate that LSD1 may provide a predictive marker for aggressive biology and a novel attractive therapeutic target for treatment of ER-negative breast cancers.

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

“…This is particularly relevant, because previous studies established LSD1 as a potential drug target for cancer treatment. [13][14][15][16][17][18]42 Continuous dox treatment of shLSD1 mice resulted in dramatic changes within different hematopoietic compartments. Mechanistically, enhanced expression of hematopoietic regulatory genes in these mice is presumably caused by the lack of LSD1 repressive activity at H3K4 residues in the gene promoters.…”

“…13 High LSD1 expression has also been reported for early relapsed prostate cancer, estrogen receptornegative breast cancer and malignant sarcomas. 6,[14][15][16] Strikingly, two recent studies report a central role of LSD1 in acute myeloid leukemia (AML). 17,18 These data identify LSD1 as a promising target for anticancer therapy.…”

Towards Sustained Silencing of HER2/neu in Cancer By Epigenetic Editing

“…For example, Lim and colleagues showed that Her2/neu is a direct target of the histone demethylase KDM1, which removes methyl groups of dimethylated H3K9 (34). In their study, siRNA-mediated knockdown of KDM1 lowered the accumulation of KDM1 on the Her2/neu promoter resulting in an increase in H3K9 methylation, a decrease in Her2/neu expression, and an inhibition in proliferation of the treated breast cancer cell lines (34). Another study by Mishra and colleagues described phosphorylation on serine 10 of histone H3 and acetylation of histone H3 and H4 in the promoter region of Her2/neu gene to be positively associated with Figure 4.…”

Impairment of prostate cancer cell growth by a selective and reversible lysine‐specific demethylase 1 inhibitor

“…17 One milligram peptide of histone H3 (residues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] carrying one or two methyl groups at lysine 4 were incubated with 2 lg of GST-LSD1 in the absence or presence of Namoline. The reaction mixture was incubated in demethylation buffer for 4 hr at 37 C and analyzed by mass spectroscopy.…”

“…20 Hence, we investigated whether Namoline also impairs the level of histone methylation and expression of those genes in AR-negative PC-3 cells. Indeed, expression of MYBL2 and CDK1 and demethylation of H3K9me1 and H3K9me2 on the promoters of those genes are significantly impaired in the presence of Namoline (Supporting Information Fig.…”