KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression

被引：52
作者：
Ali, A. [1 ,2 ]
Zhang, P. [3 ]
Liangfang, Y. [2 ]
Wenshe, S. [2 ]
Wang, H. [2 ]
Lin, X. [4 ]
Dai, Y. [1 ]
Feng, X-H [4 ]
Moses, R. [4 ]
Wang, D. [1 ]
Li, X. [4 ]
Xiao, J. [5 ]
机构：
[1] Yangzhou Univ, Coll Med, Nortern Jiangsu Peoples Hosp, Yangzhou 225001, Jiangsu, Peoples R China
[2] E China Normal Univ, Shanghai Key Lab Brain Funct Genom,Sch Life Sci, Key Lab Brain Funct Genom,Inst Biomed Sci, Shanghai Key Lab Regulatory Biol,Minist Educ, Shanghai 200241, Peoples R China
[3] Second Chengdu Municipal Hosp, Dept Pathol, Chengdu 610017, Sichuan, Peoples R China
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[5] Second Mil Med Univ, Changzheng Hosp, Dept Orthoped Oncol, Shanghai 200003, Peoples R China
来源：
CELL DEATH & DISEASE | 2015年 / 6卷
基金：
中国国家自然科学基金;
关键词：
FACTOR-BETA; TRANSCRIPTION FACTORS; C-MYC; SMAD3; FAMILY; P53; MECHANISMS; EXPRESSION; REPRESSION; PROGNOSIS;
D O I：
10.1038/cddis.2015.48
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Inhibition of tumor suppressive signaling is linked to cancer progression, metastasis and epithelial-mesenchymal transition (EMT). Transforming growth factor-beta 1 (TGF-beta)/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-beta/Smad signaling via Smad3-dependent pathway to suppress tumor progression. Intriguingly, TGF-beta/Smad3 signaling induces KLF17 expression, generating a positive feedback loop. TGF-beta/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-beta/Smad target genes. Moreover, KLF17 alters Smad3 binding pattern on chromatin. KLF17 regulates TGF-beta target genes that are Smad3-dependent. Smad3 and KLF17 physically interact with each other via KLF17 responsive elements/SBE region. Intriguingly, TGF-beta 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-beta/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-beta/Smad3 pathway. These findings define novel mechanism by which TGF-beta/Smad-KLF17 pathway mutually affect each other during cancer metastasis, provide a new model of regulation of TGF-beta/Smad signaling by KLF17 and defines new insights into anti-metastatic function of KLF17.
引用
收藏
页码：e1681 / e1681
页数：13
相关论文
共 48 条
  • [1] Differential regulation of the REGγ-proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells
    Ali, Amjad
    Wang, Zhuo
    Fu, Junjiang
    Ji, Lei
    Liu, Jiang
    Li, Lei
    Wang, Hui
    Chen, Jiwu
    Caulin, Carlos
    Myers, Jeffrey N.
    Zhang, Pei
    Xiao, Jianru
    Zhang, Bianhong
    Li, Xiaotao
    [J]. NATURE COMMUNICATIONS, 2013, 4
  • [2] [Anonymous], 2020, CA Cancer J Clin, DOI DOI 10.3322/CAAC.21590
  • [3] Kruppel-like factors: Three fingers in many pies
    Bieker, JJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (37) : 34355 - 34358
  • [4] TGFβ:: the molecular Jekyll and Hyde of cancer
    Bierie, Brian
    Moses, Harold L.
    [J]. NATURE REVIEWS CANCER, 2006, 6 (07) : 506 - 520
  • [5] Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer
    Black, AR
    Black, JD
    Azizkhan-Clifford, J
    [J]. JOURNAL OF CELLULAR PHYSIOLOGY, 2001, 188 (02) : 143 - 160
  • [6] Links between tumor suppressors:: p53 is required for TGF-β gene responses by cooperating with Smads
    Cordenonsi, M
    Dupont, S
    Maretto, S
    Insinga, A
    Imbriano, C
    Piccolo, S
    [J]. CELL, 2003, 113 (03) : 301 - 314
  • [7] Smad-dependent and Smad-independent pathways in TGF-β family signalling
    Derynck, R
    Zhang, YE
    [J]. NATURE, 2003, 425 (6958) : 577 - 584
  • [8] Identification of KLF17 as a novel epithelial to mesenchymal transition inducer via direct activation of TWIST1 in endometrioid endometrial cancer
    Dong, Peixin
    Kaneuchi, Masanori
    Xiong, Ying
    Cao, Liping
    Cai, Muyan
    Liu, Xishi
    Guo, Sun-Wei
    Ju, Jingfang
    Jia, Nan
    Konno, Yosuke
    Watari, Hidemichi
    Hosaka, Masayoshi
    Sudo, Satoko
    Sakuragi, Noriaki
    [J]. CARCINOGENESIS, 2014, 35 (04) : 760 - 768
  • [9] Convergence of p53 and TGF-beta signaling networks
    Dupont, S
    Zacchigna, L
    Adorno, M
    Soligo, S
    Volpin, D
    Piccolo, S
    Cordenonsi, M
    [J]. CANCER LETTERS, 2004, 213 (02) : 129 - 138
  • [10] Role of transforming growth factor beta in human cancer
    Elliott, RL
    Blobe, GC
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (09) : 2078 - 2093
12345