SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The comp...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-08-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04448-1 |
| _version_ | 1797451690396352512 |
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| author | Nuno Bastos Stéphanie A. Castaldo Bárbara Adem José C. Machado Carlos A. Melo Sonia A. Melo |
| author_facet | Nuno Bastos Stéphanie A. Castaldo Bárbara Adem José C. Machado Carlos A. Melo Sonia A. Melo |
| author_sort | Nuno Bastos |
| collection | DOAJ |
| description | Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression. Methods To assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples. Results In this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression. Conclusion Overall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis. |
| first_indexed | 2024-03-09T14:58:10Z |
| format | Article |
| id | doaj.art-70f87cd2d987494d8ef83b847f5f1b6e |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-09T14:58:10Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-70f87cd2d987494d8ef83b847f5f1b6e2023-11-26T14:04:36ZengBMCJournal of Translational Medicine1479-58762023-08-0121111210.1186/s12967-023-04448-1SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progressionNuno Bastos0Stéphanie A. Castaldo1Bárbara Adem2José C. Machado3Carlos A. Melo4Sonia A. Melo5i3S - Instituto de Investigação e Inovação Em Saúde, University of Portoi3S - Instituto de Investigação e Inovação Em Saúde, University of Portoi3S - Instituto de Investigação e Inovação Em Saúde, University of Portoi3S - Instituto de Investigação e Inovação Em Saúde, University of PortoThe Gurdon Institute and Department of Pathology, University of Cambridgei3S - Instituto de Investigação e Inovação Em Saúde, University of PortoAbstract Background Pancreatic ductal adenocarcinoma (PDAC) is expected to soon surpass colorectal cancer as a leading cause of cancer mortality in both males and females in the US, only lagging behind lung cancer. The lethality of PDAC is driven by late diagnosis and inefficient therapies. The complex biology of PDAC involves various cellular components, including exosomes that carry molecular information between cells. Thus, recipient cells can be reprogrammed, impacting tumorigenesis. Rab27a is a GTPase responsible for the last step of exosomes biogenesis. Hence, dissecting the mechanisms that regulate the expression of Rab27a and that control exosomes biogenesis can provide fundamental insights into the molecular underpinnings regulating PDAC progression. Methods To assess the mechanism that regulates Rab27a expression in PDAC, we used PDAC cell lines. The biological significance of these findings was validated in PDAC genetically engineered mouse models (GEMMs) and human samples. Results In this work we demonstrate in human PDAC samples and GEMMs that Rab27a expression decreases throughout the development of the disease, and that Rab27a knockout promotes disease progression. What is more, we demonstrate that Rab27a expression is epigenetically regulated in PDAC. Treatment with demethylating agents increases Rab27a expression specifically in human PDAC cell lines. We found that SMC3, a component of the cohesin complex, regulates Rab27a expression in PDAC. SMC3 methylation is present in human PDAC specimens and treatment with demethylating agents increases SMC3 expression in human PDAC cell lines. Most importantly, high levels of SMC3 methylation are associated with a worse prognosis in PDAC. Mechanistically, we identified an enhancer region within the Rab27a gene that recruits SMC3, and modulates Rab27a expression. Conclusion Overall, we dissected a mechanism that regulates Rab27a expression during PDAC progression and impacts disease prognosis.https://doi.org/10.1186/s12967-023-04448-1Pancreatic cancerRab27aExosomesSMC3 |
| spellingShingle | Nuno Bastos Stéphanie A. Castaldo Bárbara Adem José C. Machado Carlos A. Melo Sonia A. Melo SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression Journal of Translational Medicine Pancreatic cancer Rab27a Exosomes SMC3 |
| title | SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression |
| title_full | SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression |
| title_fullStr | SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression |
| title_full_unstemmed | SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression |
| title_short | SMC3 epigenetic silencing regulates Rab27a expression and drives pancreatic cancer progression |
| title_sort | smc3 epigenetic silencing regulates rab27a expression and drives pancreatic cancer progression |
| topic | Pancreatic cancer Rab27a Exosomes SMC3 |
| url | https://doi.org/10.1186/s12967-023-04448-1 |
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