title: Epigenetic Switch between SOX2 and SOX9 Regulates Cancer Cell Plasticity.
abstract: Cell differentiation within stem cell lineages can check proliferative potential, but nodal pathways that can limit tumor growth are obscure. Here, we report that lung cancer cell populations generate phenotypic and oncogenic plasticity via a switch between differentiation programs controlled by SOX2 and SOX9, thus altering proliferative and invasive capabilities. In lung cancer cells, SOX2 bound the EPCAM promoter to induce EpCAM-p21Cip1-cyclin A2 signaling, encouraging cell proliferation as well as barrier properties. In contrast, SOX9 bound the SLUG promoter to induce SLUG-mediated cell invasion with a spindle-like phenotype. Pharmacologic inhibition of HDAC elevated a SOX9-positive cell population from SOX2-positive cells, whereas ectopic expression of SOX2 inhibited SOX9 with increased H3K9me2 levels on the SOX9 promoter. In clinical specimens, the expression of SOX2 and SOX9 correlated negatively and positively with lung tumor grade, respectively. Our findings identify SOX2 and SOX9 as nodal epigenetic regulators in determining cancer cell plasticity and metastatic progression. Cancer Res; 76(23); 7036-48. ©2016 AACR.
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan. cwwu@ym.edu.tw ytchou@life.nthu.edu.tw.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chou
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Shih Sheng
authors.initials: SS
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan.|Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan.
authors.forename: Junn-Liang
authors.initials: JL
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chung
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Rung
authors.initials: YR
authors.lastname: Kao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: I-Shou
authors.initials: IS
authors.lastname: Chang
authors.affiliation: Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan. cwwu@ym.edu.tw ytchou@life.nthu.edu.tw.|Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D000066670:Cell Plasticity / Q000235:genetics*; D057890:Epigenomics; D006801:Humans; D051379:Mice; D055758:SOX9 Transcription Factor / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D055758:SOX9 Transcription Factor; D055748:SOXB1 Transcription Factors