Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer.
Loss of ZBRK1 contributes to the increase of KAP1 and promotes KAP1-mediated metastasis and invasion in cervical cancer.
复制标题
DOI：
10.1371/journal.pone.0073033
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang JM
中科院分区：
文献类型：
--
作者：
Lin LF;Li CF;Wang WJ;Yang WM;Wang DD;Chang WC;Lee WH;Wang JM
ZBRK 1是一种与乳腺癌1（BRCA 1）和KRAB-ZFP相关蛋白1（KAP 1）相互作用的锌指蛋白，已被认为通过抑制肿瘤转移/侵袭而起到肿瘤抑制剂的作用。迄今为止，BRCA 1和KAP 1如何参与ZBRK 1介导的转录抑制、转移和侵袭以及相关临床意义的详细分子机制仍不清楚。在这项研究中，我们证明了ZBRK 1的N-和C-末端结构域对于抑制宫颈癌细胞增殖和锚定非依赖性生长是重要的。具体而言，ZBRK 1的N-末端KRAB结构域通过以转录依赖性方式调节KAP 1功能在抑制转移和侵袭中显示出更重要的作用。ZBRK 1的缺失导致KAP 1表达增加，这增强了宫颈癌细胞在体外和体内的迁移和侵袭。此外，在肿瘤从原位癌进展到浸润性/转移性宫颈癌标本后，观察到ZBRK 1和KAP 1之间的表达水平呈负相关。综上所述，目前的结果表明，ZBRK 1的缺失有助于KAP 1表达的增加，增强其增强转移和侵袭的作用。
ZBRK1, a zinc finger protein that interacts with breast cancer 1 (BRCA1) and KRAB-ZFP-associated protein 1 (KAP1), has been suggested to serve as a tumor suppressor via repression of tumor metastasis/invasion. To date, the detailed molecular mechanisms for how BRCA1 and KAP1 participate in ZBRK1-mediated transcriptional repression, metastasis and invasion as well as the associated clinical relevance remain unclear. In this study, we demonstrated that both the N- and C-terminal domains of ZBRK1 are important for inhibiting cell proliferation and anchorage-independent growth in cervical cancer. Specifically, the N-terminal KRAB domain of ZBRK1 displayed a more crucial role in inhibiting metastasis and invasion through modulation of KAP1 function in a transcriptionally dependent manner. The loss of ZBRK1 results in an increase of KAP1 expression, which enhanced migration and invasion of cervical cancer cells both the in vitro and in vivo. Moreover, an inverse correlation of expression levels was observed between ZBRK1 and KAP1 following tumor progression from in situ carcinoma to invasive/metastatic cervical cancer specimens. Taken together, the current results indicate that a loss of ZBRK1 contributes to the increased expression of KAP1, potentiating its role to enhance metastasis and invasion.
登录
查看更多内容
影响因子：
3.7
作者：
Yokoe, Takeshi;Toiyama, Yuji;Kusunoki, Masato
通讯作者：
Kusunoki, Masato
影响因子：
11.2
作者：
Lin LF;Chuang CH;Li CF;Liao CC;Cheng CP;Cheng TL;Shen MR;Tseng JT;Chang WC;Lee WH;Wang JM
通讯作者：
Wang JM
影响因子：
11.2
作者：
Burga LN;Tung NM;Troyan SL;Bostina M;Konstantinopoulos PA;Fountzilas H;Spentzos D;Miron A;Yassin YA;Lee BT;Wulf GM
通讯作者：
Wulf GM
影响因子：
11.4
作者：
Wang, CG;Ivanov, A;Chen, JD
通讯作者：
Chen, JD
影响因子：
10.5
作者：
Friedman, JR;Fredericks, WJ;Rauscher, FJ
通讯作者：
Rauscher, FJ