title: Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism.
abstract: TGFβ-SMAD signaling exerts a contextual effect that suppresses malignant growth early in epithelial tumorigenesis but promotes metastasis at later stages. Longstanding challenges in resolving this functional dichotomy may uncover new strategies to treat advanced carcinomas. The Krüppel-like transcription factor, KLF10, is a pivotal effector of TGFβ/SMAD signaling that mediates antiproliferative effects of TGFβ. In this study, we show how KLF10 opposes the prometastatic effects of TGFβ by limiting its ability to induce epithelial-to-mesenchymal transition (EMT). KLF10 depletion accentuated induction of EMT as assessed by multiple metrics. KLF10 occupied GC-rich sequences in the promoter region of the EMT-promoting transcription factor SLUG/SNAI2, repressing its transcription by recruiting HDAC1 and licensing the removal of activating histone acetylation marks. In clinical specimens of lung adenocarcinoma, low KLF10 expression associated with decreased patient survival, consistent with a pivotal role for KLF10 in distinguishing the antiproliferative versus prometastatic functions of TGFβ. Our results establish that KLF10 functions to suppress TGFβ-induced EMT, establishing a molecular basis for the dichotomy of TGFβ function during tumor progression.Cancer Res; 77(9); 2387-400. ©2017 AACR.
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
authors.forename: Vivek Kumar
authors.initials: VK
authors.lastname: Mishra
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Kari
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Pitel
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Baumgart
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Naylor
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
authors.forename: Sankari
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegwitz
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Ellenrieder
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. steven.johnsen@med.uni-goettingen.de hawse.john@mayo.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Hawse
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen Center for Molecular Biosciences, Göttingen, Germany. steven.johnsen@med.uni-goettingen.de hawse.john@mayo.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D025461:Feedback, Physiological; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D018345:Mice, Knockout; D010361:Patients; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D016212:Transforming Growth Factor beta