Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway
Abstract Background Prostate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been impl...
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| Format: | Article |
| Language: | English |
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BMC
2017-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0609-y |
| _version_ | 1818500348715728896 |
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| author | Pei-Jie Zhou Wei Xue Jinliang Peng Yanqing Wang Lianzi Wei Ziqiang Yang Helen He Zhu Yu-Xiang Fang Wei-Qiang Gao |
| author_facet | Pei-Jie Zhou Wei Xue Jinliang Peng Yanqing Wang Lianzi Wei Ziqiang Yang Helen He Zhu Yu-Xiang Fang Wei-Qiang Gao |
| author_sort | Pei-Jie Zhou |
| collection | DOAJ |
| description | Abstract Background Prostate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been implicated in embryogenesis deficiency and tumorigenesis, association of polarity protein expression levels with tumor metastasis remains unclear. Methods Bioinformatics, qRT-PCR, western blot and immunohistochemical (IHC) analyses were used to examine expression of Par3, a key component of polarity-associated partitioning defective (PAR) complex, in primary and metastatic clinical PCa samples. Loss-of-function and gain-of-function studies in vitro and in vivo were performed to determine the functions of Par3 during metastasis of PCa. Co-immunoprecipitation (co-IP), western blot, immunofluorescence (IF), chromatin immunoprecipitation (ChIP) and qRT-PCR analyses were conducted to investigate the underlying mechanism for the function of Par3 on PCa metastasis. Results In this study, we found that elevated expression of Par3 is positively associated with PCa metastasis. Knockdown of Par3 inhibits PCa cell migration and invasion in vitro and tumor metastasis in vivo, whereas overexpression of Par3 yields the opposite results. Mechanistically, Par3 suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhances nuclear translocation of YAP by sequestrating KIBRA from the KIBRA/Merlin/FRMD6 complex and forming a Par3/aPKC/KIBRA complex. Stable knockdown of Par3 leads to restoration of the KIBRA/Merlin/FRMD6 complex and activation of the Hippo pathway, and then results in an inhibition on YAP nuclear translocation. In addition, in conjunction with the TEA domain (TEAD) transcription factor family, intranuclear YAP promotes the transcription of several pro-metastatic genes such as the matrix metalloproteinase (MMP) family, Zeb1, Snail1 and Twist1. Moreover, knockdown of Par3 downregulates expression of these pro-metastatic genes. Conclusions Our findings indicate that elevated expression of Par3 promotes PCa metastasis via KIBRA sequestration-mediated inactivation of the Hippo pathway to upregulate expression of pro-metastatic genes. Downregulation of Par3 expression may serve as a potential treatment approach for PCa metastasis by activating the Hippo pathway. |
| first_indexed | 2024-12-10T20:41:29Z |
| format | Article |
| id | doaj.art-e5645aa5f2024efe8dd5f579ea9e1c10 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T20:41:29Z |
| publishDate | 2017-10-01 |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e5645aa5f2024efe8dd5f579ea9e1c102022-12-22T01:34:22ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-10-0136111410.1186/s13046-017-0609-yElevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathwayPei-Jie Zhou0Wei Xue1Jinliang Peng2Yanqing Wang3Lianzi Wei4Ziqiang Yang5Helen He Zhu6Yu-Xiang Fang7Wei-Qiang Gao8State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversitySchool of Pharmacy, Shanghai Jiao Tong UniversityDepartment of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Background Prostate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been implicated in embryogenesis deficiency and tumorigenesis, association of polarity protein expression levels with tumor metastasis remains unclear. Methods Bioinformatics, qRT-PCR, western blot and immunohistochemical (IHC) analyses were used to examine expression of Par3, a key component of polarity-associated partitioning defective (PAR) complex, in primary and metastatic clinical PCa samples. Loss-of-function and gain-of-function studies in vitro and in vivo were performed to determine the functions of Par3 during metastasis of PCa. Co-immunoprecipitation (co-IP), western blot, immunofluorescence (IF), chromatin immunoprecipitation (ChIP) and qRT-PCR analyses were conducted to investigate the underlying mechanism for the function of Par3 on PCa metastasis. Results In this study, we found that elevated expression of Par3 is positively associated with PCa metastasis. Knockdown of Par3 inhibits PCa cell migration and invasion in vitro and tumor metastasis in vivo, whereas overexpression of Par3 yields the opposite results. Mechanistically, Par3 suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhances nuclear translocation of YAP by sequestrating KIBRA from the KIBRA/Merlin/FRMD6 complex and forming a Par3/aPKC/KIBRA complex. Stable knockdown of Par3 leads to restoration of the KIBRA/Merlin/FRMD6 complex and activation of the Hippo pathway, and then results in an inhibition on YAP nuclear translocation. In addition, in conjunction with the TEA domain (TEAD) transcription factor family, intranuclear YAP promotes the transcription of several pro-metastatic genes such as the matrix metalloproteinase (MMP) family, Zeb1, Snail1 and Twist1. Moreover, knockdown of Par3 downregulates expression of these pro-metastatic genes. Conclusions Our findings indicate that elevated expression of Par3 promotes PCa metastasis via KIBRA sequestration-mediated inactivation of the Hippo pathway to upregulate expression of pro-metastatic genes. Downregulation of Par3 expression may serve as a potential treatment approach for PCa metastasis by activating the Hippo pathway.http://link.springer.com/article/10.1186/s13046-017-0609-yPar3KIBRAHippo-YAP pathwayProstate cancerMetastasis |
| spellingShingle | Pei-Jie Zhou Wei Xue Jinliang Peng Yanqing Wang Lianzi Wei Ziqiang Yang Helen He Zhu Yu-Xiang Fang Wei-Qiang Gao Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway Journal of Experimental & Clinical Cancer Research Par3 KIBRA Hippo-YAP pathway Prostate cancer Metastasis |
| title | Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway |
| title_full | Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway |
| title_fullStr | Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway |
| title_full_unstemmed | Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway |
| title_short | Elevated expression of Par3 promotes prostate cancer metastasis by forming a Par3/aPKC/KIBRA complex and inactivating the hippo pathway |
| title_sort | elevated expression of par3 promotes prostate cancer metastasis by forming a par3 apkc kibra complex and inactivating the hippo pathway |
| topic | Par3 KIBRA Hippo-YAP pathway Prostate cancer Metastasis |
| url | http://link.springer.com/article/10.1186/s13046-017-0609-y |
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