Oncotarget

Priority Research Papers:

Functional characterization of lysine-specific demethylase 2 (LSD2/KDM1B) in breast cancer progression

Lin Chen, Shauna N. Vasilatos, Ye Qin, Tiffany A. Katz, Chunyu Cao, Hao Wu, Nilgun Tasdemir, Kevin M. Levine, Steffi Oesterreich, Nancy E. Davidson and Yi Huang _

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Oncotarget. 2017; 8:81737-81753. https://doi.org/10.18632/oncotarget.19387

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Abstract

Lin Chen1,2, Shauna N. Vasilatos1,3, Ye Qin1,3, Tiffany A. Katz5, Chunyu Cao1,3,8, Hao Wu1,6, Nilgun Tasdemir1,3, Kevin M. Levine1,4, Steffi Oesterreich1,3, Nancy E. Davidson7 and Yi Huang1,3

1 Women’s Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

2 School of Medicine, Tsinghua University, Beijing, P.R. China

3 Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

4 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

5 Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA

6 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China

7 Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA, USA

8 China Three Gorges University, Yichang, Hubei, P. R. China

Correspondence to:

Yi Huang, email:

Keywords: LSD2/KDM1B, breast cancer, cell growth, migration, invasion

Received: April 19, 2017 Accepted: July 03, 2017 Published: July 19, 2017

Abstract

Flavin-dependent histone demethylases govern histone H3K4 methylation and act as important chromatin modulators that are extensively involved in regulation of DNA replication, gene transcription, DNA repair, and heterochromatin gene silencing. While the activities of lysine-specific demethylase 1 (LSD1/KDM1A) in facilitating breast cancer progression have been well characterized, the roles of its homolog LSD2 (KDM1B) in breast oncogenesis are relatively less understood. In this study, we showed that LSD2 protein level was significantly elevated in malignant breast cell lines compared with normal breast epithelial cell line. TCGA- Oncomine database showed that LSD2 expression is significantly higher in basal-like breast tumors compared to other breast cancer subtypes or normal breast tissue. Overexpression of LSD2 in MDA-MB-231 cells significantly altered the expression of key important epigenetic modifiers such as LSD1, HDAC1/2, and DNMT3B; promoted cellular proliferation; and augmented colony formation in soft agar; while attenuating motility and invasion. Conversely, siRNA-mediated depletion of endogenous LSD2 hindered growth of multiple breast cancer cell lines while shRNA-mediated LSD2 depletion augmented motility and invasion. Moreover, LSD2 overexpression in MDA-MB-231 cells facilitated mammosphere formation, enriched the subpopulation of CD49f+/EpCAM- and ALDHhigh, and induced the expression of pluripotent stem cell markers, NANOG and SOX2. In xenograft studies using immune-compromised mice, LSD2-overexpressing MDA-MB-231 cells displayed accelerated tumor growth but significantly fewer lung metastases than controls. Taken together, our findings provide novel insights into the critical and multifaceted roles of LSD2 in the regulation of breast cancer progression and cancer stem cell enrichment.


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