机构：[1]Nortern Jiangsu People’s Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu 225001, China江苏省人民医院[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[3]Department of Pathology, the Second Chengdu Municipal Hospital, Chengdu, Sichuan 610017, China[4]Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA[5]Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China
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.
基金：
National Basic Research
Program (2011CB504200), This work was supported in part by a joint China-Canada
grant from the National Natural Science Foundation of China Grants (81261120555).
This work was also supported by the National Natural Science Foundation of China
Grants (31200878), the Shanghai natural science foundation (12ZR1409300) and the
Applied Basic Research Program of Science and Technology Department of Sichuan
Province (2015JY0038).
第一作者机构：[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
共同第一作者：
通讯作者：
通讯机构：[1]Nortern Jiangsu People’s Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu 225001, China[4]Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA[5]Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China[*1]Nortern Jiangsu People’s Hospital (Medical College of Yangzhou University), Yangzhou, Jiangsu, 225001, China[*2]Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China[*3]Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
推荐引用方式(GB/T 7714)：
Ali A,Zhang P,Liangfang Y,et al.KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression.[J].CELL DEATH & DISEASE.2015,6:doi:10.1038/cddis.2015.48.
APA：
Ali A,Zhang P,Liangfang Y,Wenshe S,Wang H...&Xiao J.(2015).KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression..CELL DEATH & DISEASE,6,
MLA：
Ali A,et al."KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression.".CELL DEATH & DISEASE 6.(2015)
生物学