KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression.
KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression.
复制标题
DOI：
10.1038/cddis.2015.48
复制
发表时间：
2015-03-12
影响因子：
9
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Ali A;Zhang P;Liangfang Y;Wenshe S;Wang H;Lin X;Dai Y;Feng XH;Moses R;Wang D;Li X;Xiao J
抑制肿瘤抑制信号与肿瘤的进展、转移和上皮-间充质转化(EMT)有关。转化生长因子-β-1(转化生长因子-β)/Smad信号在肿瘤抑制中起重要作用。Kruppel-like-factor17(KLF17)是转移和EMT的负性调节因子。然而，KLF17抑制肿瘤和抗转移功能的潜在机制仍不清楚。在这里，我们发现KLF17在通过Smad3依赖的途径增强转化生长因子-β/Smad信号以抑制肿瘤进展方面发挥了不可或缺的作用。有趣的是，转化生长因子-β/Smad3信号诱导KLF17的表达，产生一个正反馈循环。转化生长因子-β/Smad3-KLF17环在肿瘤细胞的抗转移和抑瘤作用中起重要作用。从机制上讲，沉默KLF17减少了Smad3-DNA复合体在Smad结合元件上的形成，并影响了转化生长因子-β/Smad靶基因的表达。此外，KLF17还改变了染色质上的Smad3结合模式。KLF17调控Smad3依赖的转化生长因子-β靶基因。SMAD3和KLF17通过KLF17反应元件/SBE区相互作用。有趣的是，转化生长因子-β刺激KLF17在染色质上向转移相关基因的亚群募集。在功能上，KLF17的缺失增强了癌细胞的致瘤特性。KLF17对转化生长因子-β/Smad信号的完全细胞抑制功能至关重要。临床上，KLF17在进展期肝细胞癌中的表达显著降低。KLF17与癌组织中Smad3水平呈正相关。我们的数据表明，KLF17活性的增强对于针对转化生长因子-β/Smad3通路的靶向治疗具有重要的治疗意义。这些发现明确了转化生长因子-β/Smad-KLF17信号通路在肿瘤转移过程中相互影响的新机制，为KLF17对转化生长因子-β/Smad信号的调控提供了新的模型，并对KLF17的抗转移功能有了新的认识。
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.
登录
查看更多内容
影响因子：
8
作者：
Fink, SP;Mikkola, D;Markowitz, S
通讯作者：
Markowitz, S
影响因子：
11.4
作者：
Huang, Tao;David, Laurent;Hinck, Andrew P.
通讯作者：
Hinck, Andrew P.
影响因子：
21.3
作者：
Gumireddy K;Li A;Gimotty PA;Klein-Szanto AJ;Showe LC;Katsaros D;Coukos G;Zhang L;Huang Q
通讯作者：
Huang Q
影响因子：
12.3
作者：
Iwanicki MP;Brugge JS
通讯作者：
Brugge JS
影响因子：
6.4
作者：
Ferlay, Jacques;Shin, Hai-Rim;Parkin, Donald Maxwell
通讯作者：
Parkin, Donald Maxwell