Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology.
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.
Lim
Soyoung
S
Institute of Pathology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
Janzer
Andreas
A
Becker
Astrid
A
Zimmer
Andreas
A
Schüle
Roland
R
Buettner
Reinhard
R
Kirfel
Jutta
J
D000230:Adenocarcinoma / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor / Q000201:enzymology; D047369:Chromatin Immunoprecipitation; D056751:Cyclin A2 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018734:Genes, erbB-2; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000032:analysis; D006801:Humans; D008745:Methylation; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis
D014408:Biomarkers, Tumor; C503721:CCNA2 protein, human; C493956:CDKN1A protein, human; D056751:Cyclin A2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D056466:Histone Demethylases; C495195:KDM1A protein, human