Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer
Abstract Background Caveolae proteins play diverse roles in cancer development and progression. In prostate cancer, non‐caveolar caveolin‐1 (CAV1) promotes metastasis, while CAVIN1 attenuates CAV1‐induced metastasis. Here, we unveil a novel mechanism linking CAV1 to selective loading of exosomes wit...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-04-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.381 |
| _version_ | 1818958096045703168 |
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| author | Harley Robinson Jayde E. Ruelcke Amanda Lewis Charles S. Bond Archa H. Fox Vandhana Bharti Shivangi Wani Nicole Cloonan Andrew Lai David Margolin Li Li Carlos Salomon Renée S. Richards Aine Farrell Robert A. Gardiner Robert G. Parton Alexandre S. Cristino Michelle M. Hill |
| author_facet | Harley Robinson Jayde E. Ruelcke Amanda Lewis Charles S. Bond Archa H. Fox Vandhana Bharti Shivangi Wani Nicole Cloonan Andrew Lai David Margolin Li Li Carlos Salomon Renée S. Richards Aine Farrell Robert A. Gardiner Robert G. Parton Alexandre S. Cristino Michelle M. Hill |
| author_sort | Harley Robinson |
| collection | DOAJ |
| description | Abstract Background Caveolae proteins play diverse roles in cancer development and progression. In prostate cancer, non‐caveolar caveolin‐1 (CAV1) promotes metastasis, while CAVIN1 attenuates CAV1‐induced metastasis. Here, we unveil a novel mechanism linking CAV1 to selective loading of exosomes with metastasis‐promoting microRNAs. Results We identify hnRNPK as a CAV1‐regulated microRNA binding protein. In the absence of CAVIN1, non‐caveolar CAV1 drives localisation of hnRPNK to multi‐vesicular bodies (MVBs), recruiting AsUGnA motif‐containing miRNAs and causing their release within exosomes. This process is dependent on the lipid environment of membranes as shown by cholesterol depletion using methyl‐β‐cyclodextrin or by treatment with n‐3 polyunsaturated fatty acids. Consistent with a role in bone metastasis, knockdown of hnRNPK in prostate cancer PC3 cells abolished the ability of PC3 extracellular vesicles (EV) to induce osteoclastogenesis, and biofluid EV hnRNPK is elevated in metastatic prostate and colorectal cancer. Conclusions Taken together, these results support a novel pan‐cancer mechanism for CAV1‐driven exosomal release of hnRNPK and associated miRNA in metastasis, which is modulated by the membrane lipid environment. |
| first_indexed | 2024-12-20T11:20:18Z |
| format | Article |
| id | doaj.art-a1d967901fc5495aab625a28d3f45eea |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-20T11:20:18Z |
| publishDate | 2021-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-a1d967901fc5495aab625a28d3f45eea2022-12-21T19:42:32ZengWileyClinical and Translational Medicine2001-13262021-04-01114n/an/a10.1002/ctm2.381Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancerHarley Robinson0Jayde E. Ruelcke1Amanda Lewis2Charles S. Bond3Archa H. Fox4Vandhana Bharti5Shivangi Wani6Nicole Cloonan7Andrew Lai8David Margolin9Li Li10Carlos Salomon11Renée S. Richards12Aine Farrell13Robert A. Gardiner14Robert G. Parton15Alexandre S. Cristino16Michelle M. Hill17The University of Queensland Diamantina Institute The University of Queensland Woolloongabba Queensland AustraliaThe University of Queensland Diamantina Institute The University of Queensland Woolloongabba Queensland AustraliaSchool of Molecular Sciences The University of Western Australia Crawley WA AustraliaSchool of Molecular Sciences The University of Western Australia Crawley WA AustraliaSchool of Molecular Sciences The University of Western Australia Crawley WA AustraliaQIMR Berghofer Medical Research Institute Brisbane Queensland AustraliaQIMR Berghofer Medical Research Institute Brisbane Queensland AustraliaQIMR Berghofer Medical Research Institute Brisbane Queensland AustraliaUniversity of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital The University of Queensland Brisbane Queensland AustraliaMaternal‐Fetal Medicine, Department of Obstetrics and Gynecology Ochsner Clinic Foundation New Orleans USAMaternal‐Fetal Medicine, Department of Obstetrics and Gynecology Ochsner Clinic Foundation New Orleans USAUniversity of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital The University of Queensland Brisbane Queensland AustraliaQIMR Berghofer Medical Research Institute Brisbane Queensland AustraliaUniversity of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital The University of Queensland Brisbane Queensland AustraliaUniversity of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital The University of Queensland Brisbane Queensland AustraliaInstitute for Molecular Bioscience The University of Queensland St Lucia Queensland AustraliaThe University of Queensland Diamantina Institute The University of Queensland Woolloongabba Queensland AustraliaThe University of Queensland Diamantina Institute The University of Queensland Woolloongabba Queensland AustraliaAbstract Background Caveolae proteins play diverse roles in cancer development and progression. In prostate cancer, non‐caveolar caveolin‐1 (CAV1) promotes metastasis, while CAVIN1 attenuates CAV1‐induced metastasis. Here, we unveil a novel mechanism linking CAV1 to selective loading of exosomes with metastasis‐promoting microRNAs. Results We identify hnRNPK as a CAV1‐regulated microRNA binding protein. In the absence of CAVIN1, non‐caveolar CAV1 drives localisation of hnRPNK to multi‐vesicular bodies (MVBs), recruiting AsUGnA motif‐containing miRNAs and causing their release within exosomes. This process is dependent on the lipid environment of membranes as shown by cholesterol depletion using methyl‐β‐cyclodextrin or by treatment with n‐3 polyunsaturated fatty acids. Consistent with a role in bone metastasis, knockdown of hnRNPK in prostate cancer PC3 cells abolished the ability of PC3 extracellular vesicles (EV) to induce osteoclastogenesis, and biofluid EV hnRNPK is elevated in metastatic prostate and colorectal cancer. Conclusions Taken together, these results support a novel pan‐cancer mechanism for CAV1‐driven exosomal release of hnRNPK and associated miRNA in metastasis, which is modulated by the membrane lipid environment.https://doi.org/10.1002/ctm2.381cancercargoepigeneticsextracellular vesiclehnRNPKlipid raft |
| spellingShingle | Harley Robinson Jayde E. Ruelcke Amanda Lewis Charles S. Bond Archa H. Fox Vandhana Bharti Shivangi Wani Nicole Cloonan Andrew Lai David Margolin Li Li Carlos Salomon Renée S. Richards Aine Farrell Robert A. Gardiner Robert G. Parton Alexandre S. Cristino Michelle M. Hill Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer Clinical and Translational Medicine cancer cargo epigenetics extracellular vesicle hnRNPK lipid raft |
| title | Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer |
| title_full | Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer |
| title_fullStr | Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer |
| title_full_unstemmed | Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer |
| title_short | Caveolin‐1‐driven membrane remodelling regulates hnRNPK‐mediated exosomal microRNA sorting in cancer |
| title_sort | caveolin 1 driven membrane remodelling regulates hnrnpk mediated exosomal microrna sorting in cancer |
| topic | cancer cargo epigenetics extracellular vesicle hnRNPK lipid raft |
| url | https://doi.org/10.1002/ctm2.381 |
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