Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer
Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer
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DOI：
10.1038/onc.2017.321
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发表时间：
2018-01-11
期刊：
影响因子：
8
通讯作者：
Takata, T.
中科院分区：
文献类型：
--
作者：
Ando, T.;Charindra, D.;Takata, T.
金属蛋白酶组织抑制因子-1(TIMP-1)是TIMP家族(TIMP-1~TIMP-4)的成员之一，在多种肿瘤中高表达，并与其受体CD63和整合素β1形成复合体。然而，TIMP-1的确切致癌机制尚不清楚。是相关蛋白(YAP)和带有PDZ结合基序的转录共激活因子(TAZ)是促进细胞增殖相关基因转录的转录共激活因子。但YAP/TAZ在肿瘤中异常激活的机制尚不完全清楚。在这里，我们发现TIMP-1激活YAP/TAZ作为促进细胞增殖的新的下游靶点。TIMP-1-CD63-整合素β1轴激活Src，促进RhoA介导的F-肌动蛋白组装，导致LATS1/2失活。这导致YAP/TAZ的磷酸化不足、蛋白质稳定和核易位(YAP/TAZ激活)；CTGF的产生；以及细胞增殖。此外，TIMP-1-YAP/TAZ轴在各种类型的癌细胞或组织中被异常激活。TIMP-1基因敲除通过在癌细胞中失活YAP/TAZ来抑制细胞增殖。本研究发现TIMP-1通过激活YAP/TAZ来促进肿瘤细胞的增殖，提示TIMP-1-YAP/TAZ轴可能是癌症患者潜在的药物靶点。
Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin beta 1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin beta 1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.