ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes

Gi-Cheon Kim; Choong-Gu Lee; Ravi Verma; Dipayan Rudra; Taemook Kim; Keunsoo Kang; Jong Hee Nam; Young Kim; Sin-Hyeog Im; Ho-Keun Kwon

doi:10.3389/fonc.2020.00642

ETS1 Suppresses Tumorigenesis of Human Breast Cancer via Trans-Activation of Canonical Tumor Suppressor Genes

Front Oncol. 2020 May 14:10:642. doi: 10.3389/fonc.2020.00642. eCollection 2020.

Authors

Gi-Cheon Kim^{1

2}, Choong-Gu Lee³, Ravi Verma⁴, Dipayan Rudra⁴, Taemook Kim⁵, Keunsoo Kang⁶, Jong Hee Nam⁷, Young Kim⁸, Sin-Hyeog Im^{4

9}, Ho-Keun Kwon^{1

2

10}

Affiliations

¹ Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, South Korea.
² Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
³ Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung Institute of Natural Products, Gangneung, South Korea.
⁴ Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, South Korea.
⁵ Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
⁶ Department of Microbiology, College of Natural Sciences, Dankook University, Cheonan, South Korea.
⁷ Department of Pathology, Chonnam National University Medical School, Gwangju, South Korea.
⁸ Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju, South Korea.
⁹ Division of Integrative Biosciences and Biotechnology, Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea.
¹⁰ Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea.

Abstract

ETS1 has shown dichotomous roles as an oncogene and a tumor suppressor gene in diverse cancers, but its functionality in breast cancer tumorigenesis still remains unclear. We utilized the Cancer Genome Atlas (TCGA) database to analyze comprehensive functions of ETS1 in human breast cancer (BRCA) patients by investigating its expression patterns and methylation status in relation to clinical prognosis. ETS1 expression was significantly diminished by hyper-methylation of the ETS1 promoter region in specimens from BRCA patients compared to a healthy control group. Moreover, ETS1 ^high BRCA patients showed better prognosis and longer survival compared to ETS1 ^low BRCA patients. Consistent with clinical evidence, comparative transcriptome analysis combined with CRISPR/Cas9 or shRNA based perturbation of ETS1 expression revealed direct as well as indirect mechanisms of ETS1 that hinder tumorigenesis of BRCA cells. Taken together, our study enlightens a novel function of ETS1 as a tumor suppressor in breast cancer cells.

Keywords: DNA methylation; ETS1; breast cancer; regulatory elements; tumor suppressor.