title: KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression.
abstract: Inhibition of tumor suppressive signaling is linked to cancer progression, metastasis and epithelial-mesenchymal transition (EMT). Transforming growth factor-β1 (TGF-β)/Smad signaling plays an important role in tumor suppression. Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and EMT. However, underlying mechanisms leading to tumor suppressive and anti-metastatic function of KLF17 still remains unknown. Here, we show that KLF17 plays an integral role in potentiating TGF-β/Smad signaling via Smad3-dependent pathway to suppress tumor progression. Intriguingly, TGF-β/Smad3 signaling induces KLF17 expression, generating a positive feedback loop. TGF-β/Smad3-KLF17 loop is critical for anti-metastasis and tumor inhibition in cancer cells. Mechanistically, silencing KLF17 reduced Smad3-DNA complex formation on Smad binding element (SBE) and affects the expression of TGF-β/Smad target genes. Moreover, KLF17 alters Smad3 binding pattern on chromatin. KLF17 regulates TGF-β target genes that are Smad3-dependent. Smad3 and KLF17 physically interact with each other via KLF17 responsive elements/SBE region. Intriguingly, TGF-β stimulates the recruitment of KLF17 on chromatin to subsets of metastasis-associated genes. Functionally, depletion of KLF17 enhanced tumorigenic features in cancer cells. KLF17 is critical for full cytostatic function of TGF-β/Smad signaling. Clinically, KLF17 expression significantly decreases during advance HCC. KLF17 shows positive correlation with Smad3 levels in cancer samples. Our data shows that enhance KLF17 activity has important therapeutic implications for targeted-therapies aimed at TGF-β/Smad3 pathway. These findings define novel mechanism by which TGF-β/Smad-KLF17 pathway mutually affect each other during cancer metastasis, provide a new model of regulation of TGF-β/Smad signaling by KLF17 and defines new insights into anti-metastatic function of KLF17.
authors.affiliation: 1] Nortern Jiangsu People's Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu 225001, China [2] Shanghai Key Laboratory of Regulatory Biology, Key Laboratory of Brain Functional Genomics (Ministry of Education), Shanghai Key Laboratory of Brain Functional Genomics, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: A
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Pathology, the Second Chengdu Municipal Hospital, Chengdu, Sichuan 610017, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Key Laboratory of Brain Functional Genomics (Ministry of Education), Shanghai Key Laboratory of Brain Functional Genomics, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liangfang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Key Laboratory of Brain Functional Genomics (Ministry of Education), Shanghai Key Laboratory of Brain Functional Genomics, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: S
authors.initials: S
authors.lastname: Wenshe
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Key Laboratory of Brain Functional Genomics (Ministry of Education), Shanghai Key Laboratory of Brain Functional Genomics, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.affiliation: Nortern Jiangsu People's Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu 225001, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: X-h
authors.initials: XH
authors.lastname: Feng
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: R
authors.initials: R
authors.lastname: Moses
authors.affiliation: Nortern Jiangsu People's Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu 225001, China.
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiao
mesh_terms: D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C510638:KLF17 protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1