∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1
Abstract ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in squamous cell carcinoma, loss of ΔNp63α expr...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01789-0 |
| _version_ | 1797355962036649984 |
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| author | Amjad A. Aljagthmi Akshay Hira Jin Zhang Mariana Cooke Marcelo G. Kazanietz Madhavi P. Kadakia |
| author_facet | Amjad A. Aljagthmi Akshay Hira Jin Zhang Mariana Cooke Marcelo G. Kazanietz Madhavi P. Kadakia |
| author_sort | Amjad A. Aljagthmi |
| collection | DOAJ |
| description | Abstract ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in squamous cell carcinoma, loss of ΔNp63α expression is associated with increased tumor cell invasion and metastasis. We recently identified a ΔNp63α/miR-320a/PKCγ signaling axis that regulates cancer cell invasion by inhibiting phosphorylation of the small GTPase Rac1, a master switch of cell motility that positively regulates cell invasion in multiple human cancers. In this study, we identified a novel mechanism by which ΔNp63α negatively regulates Rac1 activity, by inhibiting the expression of the Rac-specific Guanine Exchange Factor PREX1. ΔNp63α knockdown in multiple squamous cell carcinoma cell lines leads to increased Rac1 activation, which is abrogated by treatment with the Rac1 inhibitor NSC23766. Furthermore, ΔNp63α negatively regulates PREX1 transcript and protein levels. Using a Rac-GEF activation assay, we also showed that ΔNp63α reduces the levels of active PREX1. The inhibition of the PREX1-Rac1 signaling axis by ΔNp63α leads to impaired cell invasion, thus establishing the functional relevance of this link. Our results elucidated a novel molecular mechanism by which ΔNp63α negatively affects cancer cell invasion and identifies the ΔNp63α/Rac1 axis as a potential target for metastasis. |
| first_indexed | 2024-03-08T14:18:45Z |
| format | Article |
| id | doaj.art-055e3aa304f34c3ab1657697ec0e9d62 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-08T14:18:45Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-055e3aa304f34c3ab1657697ec0e9d622024-01-14T12:12:07ZengNature Publishing GroupCell Death Discovery2058-77162024-01-011011810.1038/s41420-023-01789-0∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1Amjad A. Aljagthmi0Akshay Hira1Jin Zhang2Mariana Cooke3Marcelo G. Kazanietz4Madhavi P. Kadakia5Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State UniversityDepartment of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State UniversityDepartment of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State UniversityDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State UniversityAbstract ΔNp63α, a member of the p53 family of transcription factors, plays a critical role in maintaining the proliferative potential of stem cells in the stratified epithelium. Although ΔNp63α is considered an oncogene and is frequently overexpressed in squamous cell carcinoma, loss of ΔNp63α expression is associated with increased tumor cell invasion and metastasis. We recently identified a ΔNp63α/miR-320a/PKCγ signaling axis that regulates cancer cell invasion by inhibiting phosphorylation of the small GTPase Rac1, a master switch of cell motility that positively regulates cell invasion in multiple human cancers. In this study, we identified a novel mechanism by which ΔNp63α negatively regulates Rac1 activity, by inhibiting the expression of the Rac-specific Guanine Exchange Factor PREX1. ΔNp63α knockdown in multiple squamous cell carcinoma cell lines leads to increased Rac1 activation, which is abrogated by treatment with the Rac1 inhibitor NSC23766. Furthermore, ΔNp63α negatively regulates PREX1 transcript and protein levels. Using a Rac-GEF activation assay, we also showed that ΔNp63α reduces the levels of active PREX1. The inhibition of the PREX1-Rac1 signaling axis by ΔNp63α leads to impaired cell invasion, thus establishing the functional relevance of this link. Our results elucidated a novel molecular mechanism by which ΔNp63α negatively affects cancer cell invasion and identifies the ΔNp63α/Rac1 axis as a potential target for metastasis.https://doi.org/10.1038/s41420-023-01789-0 |
| spellingShingle | Amjad A. Aljagthmi Akshay Hira Jin Zhang Mariana Cooke Marcelo G. Kazanietz Madhavi P. Kadakia ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 Cell Death Discovery |
| title | ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 |
| title_full | ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 |
| title_fullStr | ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 |
| title_full_unstemmed | ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 |
| title_short | ∆Np63α inhibits Rac1 activation and cancer cell invasion through suppression of PREX1 |
| title_sort | ∆np63α inhibits rac1 activation and cancer cell invasion through suppression of prex1 |
| url | https://doi.org/10.1038/s41420-023-01789-0 |
| work_keys_str_mv | AT amjadaaljagthmi np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 AT akshayhira np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 AT jinzhang np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 AT marianacooke np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 AT marcelogkazanietz np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 AT madhavipkadakia np63ainhibitsrac1activationandcancercellinvasionthroughsuppressionofprex1 |