title: SLUG is required for SOX9 stabilization and functions to promote cancer stem cells and metastasis in human lung carcinoma.
abstract: Cancer stem cells (CSCs) are a promising target for cancer therapy, particularly for metastatic lung cancers, but how CSCs are regulated is largely unknown. We identify two proteins, SLUG (encoded by SNAI2 gene) and SOX9, which are associated with advanced stage lung cancers and are implicated in the regulation of CSCs. Inhibition of either SLUG or SOX9 sufficiently inhibits CSCs in human lung cancer cells and attenuates experimental lung metastasis in a xenograft mouse model. Correlation between SLUG and SOX9 levels was observed remarkably, we therefore sought to explore their mechanistic relationship and regulation. SLUG, beyond its known function as an epithelial-mesenchymal transition transcription factor, was found to regulate SOX9 by controlling its stability via a post-translational modification process. SLUG interacts directly with SOX9 and prevents it from ubiquitin-mediated proteasomal degradation. SLUG expression and binding are necessary for SOX9 promotion of lung CSCs and metastasis in a mouse model. Together, our findings provide a novel mechanistic insight into the regulation of CSCs via SLUG-SOX9 regulatory axis, which represents a potential novel target for CSC therapy that may overcome cancer chemoresistance and relapse.
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.|Pharmaceutical and Pharmacological Sciences Program, West Virginia University, Morgantwon, WV, USA.|Mary Babb Randolph Cancer Center, West Virginia University, Mogantown, WV, USA.
authors.forename: S
authors.identifier: 0000-0002-1639-4935
authors.initials: S
authors.lastname: Luanpitpong
authors.affiliation: Stem Cell and Tissue Engineering Laboratory, West Virginia University, Morgantown, WV, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Pharmaceutical and Pharmacological Sciences Program, West Virginia University, Morgantwon, WV, USA.
authors.forename: A
authors.initials: A
authors.lastname: Manke
authors.affiliation: Flow Cytometry Core Facility, West Virginia University, Morgantown, WV, USA.
authors.forename: K
authors.initials: K
authors.lastname: Brundage
authors.affiliation: Animal Models and Imaging Facility, West Virginia University, Morgantown, WV, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ellis
authors.affiliation: Animal Models and Imaging Facility, West Virginia University, Morgantown, WV, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: McLaughlin
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Angsutararux
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: N
authors.initials: N
authors.lastname: Chanthra
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University, Mogantown, WV, USA.
authors.forename: M
authors.initials: M
authors.lastname: Voronkova
authors.affiliation: Natural Science Division, Alderson Broaddus University, Philippi, WV, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, WV, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Cell-Based Drug and Health Product Development Research Unit, Chulalongkorn University, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Chanvorachote
authors.affiliation: Stem Cell and Tissue Engineering Laboratory, West Virginia University, Morgantown, WV, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pei
authors.affiliation: Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Issaragrisil
authors.affiliation: Pharmaceutical and Pharmacological Sciences Program, West Virginia University, Morgantwon, WV, USA.|Mary Babb Randolph Cancer Center, West Virginia University, Mogantown, WV, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D055550:Protein Stability; D059748:Proteolysis; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000604407:SNAI1 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D000071250:Snail Family Transcription Factors