YAP1 regulates ABCG2 and cancer cell side population in human lung cancer cells.
YAP1 regulates ABCG2 and cancer cell side population in human lung cancer cells.
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DOI：
10.18632/oncotarget.13686
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发表时间：
2017-01-17
期刊：
影响因子：
--
通讯作者：
You L
中科院分区：
文献类型：
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作者：
Dai Y;Liu S;Zhang WQ;Yang YL;Hang P;Wang H;Cheng L;Hsu PC;Wang YC;Xu Z;Jablons DM;You L
一小群称为癌症起始细胞或癌症干细胞（CSC）的癌细胞参与耐药性，转移和癌症复发。寻找调控CSC的通路对临床治疗具有重要意义。ATP结合盒亚家族G成员2（ABCG 2）在侧群（SP）细胞形成中起作用，并有助于常见形式的癌症的化疗耐药性。YAP 1是Hippo信号通路的一个重要转录因子，在器官大小调控和肿瘤发生中起重要作用。在本研究中，我们发现ABCG 2和YAP 1在肺癌SP细胞中均过表达。通过siRNA干扰YAP 1的表达，减弱了ABCG 2转录本的表达，并显著降低了肺癌细胞中SP细胞的百分比和球体形成。肺癌中YAP 1的过表达导致ABCG 2表达增加，SP细胞百分比增加。然而，在纯化的non-SP细胞中过表达YAP 1并不增加ABCG 2表达和SP细胞的百分比，这可能是由于通过磷酸化抑制雅普活性。YAP 1通过与ABCG 2的启动子结合直接转录调控ABCG 2。此外，YAP 1抑制剂维替泊芬和YAP 1 siRNA通过抑制肺癌细胞中的YAP 1而下调ABCG 2水平，并使其对化疗药物阿霉素敏感。我们的研究为YAP 1增加了一个新的功能，该功能可能通过调节ABCG 2和肺癌侧群细胞形成与耐药性和癌症治疗相关。
A small population of cancer cells called cancer-initiating cells or cancer stem cells (CSCs) are involved in drug resistance, metastasis, and cancer relapse. Finding pathways that regulate CSC is very important for clinical therapy. ATP-binding cassette sub-family G member 2 (ABCG2) plays a role in side population (SP) cell formation and contributes to chemotherapy resistance in common forms of cancer. Yes-associated protein 1 (YAP1) is a major transcriptional effector of the Hippo pathway, which plays important roles in organ size control and tumorigenesis. In this study, we found ABCG2 and YAP1 were both overexpressed in lung cancer SP cells. Disruption of YAP1 expression by siRNA attenuated the expression of ABCG2 transcript and significantly reduced the percentage of SP cells and sphere formation in lung cancer cells. Overexpression of YAP1 in lung cancers led to an increase in ABCG2 expression and increased the percentage of SP cells. However, overexpression of YAP1 in purified non-SP cells did not increase ABCG2 expression and the percentage of SP cells, which may be due to the inhibition of YAP activity through phosphorylation. YAP1 directly transcriptionally regulated ABCG2 by binding to the promoter of ABCG2. Moreover, the YAP1 inhibitor verteporfin and YAP1 siRNA downregulated ABCG2 level through inhibition of YAP1 in lung cancer cells and sensitized them to the chemotherapy drug doxorubicin. Our study adds a new function for YAP1 that may be relevant to drug resistance and cancer therapy through regulation of ABCG2 and side population cell formation in lung cancer.