UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells
Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug‐induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin‐2 (mot‐2) is a dominant oncoprotein in several tumors, including col...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-10-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12372 |
| _version_ | 1818408720912089088 |
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| author | Sanam Sane Andre Hafner Rekha Srinivasan Daniall Masood John l. Slunecka Collin J. Noldner Alex D. Hanson Taylor Kruisselbrink Xuejun Wang Yiyang Wang Jun Yin Khosrow Rezvani |
| author_facet | Sanam Sane Andre Hafner Rekha Srinivasan Daniall Masood John l. Slunecka Collin J. Noldner Alex D. Hanson Taylor Kruisselbrink Xuejun Wang Yiyang Wang Jun Yin Khosrow Rezvani |
| author_sort | Sanam Sane |
| collection | DOAJ |
| description | Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug‐induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin‐2 (mot‐2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot‐2 enhances tumor cell invasion and migration. Thus, mot‐2 is considered a potential therapeutic target in several cancer types. The current study investigated the biological role of a ubiquitin‐like protein called UBXN2A in the regulation of mot‐2 turnover. An orthogonal ubiquitin transfer technology followed by immunoprecipitation, in vitro ubiquitination, and Magnetic Beads TUBE2 pull‐down experiments revealed that UBXN2A promotes carboxyl terminus of the HSP70‐interacting protein (CHIP)‐dependent ubiquitination of mot‐2. We subsequently showed that UBXN2A increases proteasomal degradation of mot‐2. A subcellular compartmentalization experiment revealed that induced UBXN2A decreases the level of mot‐2 and its chaperone partner, HSP60. Pharmacological upregulation of UBXN2A using a small molecule, veratridine (VTD), decreases the level of mot‐2 in cancer cells. Consistent with the in vitro results, UBXN2A+/− mice exhibited selective elevation of mot‐2 in colon tissues. An in vitro Anti‐K48 TUBE isolation approach showed that recombinant UBXN2A enhances proteasomal degradation of mot‐2 in mouse colon tissues. Finally, we observed enhanced association of CHIP with the UBXN2A‐mot‐2 complex in tumors in an azoxymethane/dextran sulfate sodium‐induced mouse CRC model. The existence of a multiprotein complex containing UBXN2A, CHIP, and mot‐2 suggests a synergistic tumor suppressor activity of UBXN2A and CHIP in mot‐2‐enriched tumors. This finding validates the UBXN2A‐CHIP axis as a novel and potential therapeutic target in CRC. |
| first_indexed | 2024-12-14T09:48:13Z |
| format | Article |
| id | doaj.art-8142dff1e9974bd79806dd9c3d84c9be |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-14T09:48:13Z |
| publishDate | 2018-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-8142dff1e9974bd79806dd9c3d84c9be2022-12-21T23:07:35ZengWileyMolecular Oncology1574-78911878-02612018-10-0112101753177710.1002/1878-0261.12372UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cellsSanam Sane0Andre Hafner1Rekha Srinivasan2Daniall Masood3John l. Slunecka4Collin J. Noldner5Alex D. Hanson6Taylor Kruisselbrink7Xuejun Wang8Yiyang Wang9Jun Yin10Khosrow Rezvani11Division of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USADepartment of Chemistry Center for Diagnostics & Therapeutics Georgia State University Atlanta GA USADepartment of Chemistry Center for Diagnostics & Therapeutics Georgia State University Atlanta GA USADivision of Basic Biomedical Sciences Sanford School of Medicine The University of South Dakota Vermillion SD USAOverexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug‐induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin‐2 (mot‐2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot‐2 enhances tumor cell invasion and migration. Thus, mot‐2 is considered a potential therapeutic target in several cancer types. The current study investigated the biological role of a ubiquitin‐like protein called UBXN2A in the regulation of mot‐2 turnover. An orthogonal ubiquitin transfer technology followed by immunoprecipitation, in vitro ubiquitination, and Magnetic Beads TUBE2 pull‐down experiments revealed that UBXN2A promotes carboxyl terminus of the HSP70‐interacting protein (CHIP)‐dependent ubiquitination of mot‐2. We subsequently showed that UBXN2A increases proteasomal degradation of mot‐2. A subcellular compartmentalization experiment revealed that induced UBXN2A decreases the level of mot‐2 and its chaperone partner, HSP60. Pharmacological upregulation of UBXN2A using a small molecule, veratridine (VTD), decreases the level of mot‐2 in cancer cells. Consistent with the in vitro results, UBXN2A+/− mice exhibited selective elevation of mot‐2 in colon tissues. An in vitro Anti‐K48 TUBE isolation approach showed that recombinant UBXN2A enhances proteasomal degradation of mot‐2 in mouse colon tissues. Finally, we observed enhanced association of CHIP with the UBXN2A‐mot‐2 complex in tumors in an azoxymethane/dextran sulfate sodium‐induced mouse CRC model. The existence of a multiprotein complex containing UBXN2A, CHIP, and mot‐2 suggests a synergistic tumor suppressor activity of UBXN2A and CHIP in mot‐2‐enriched tumors. This finding validates the UBXN2A‐CHIP axis as a novel and potential therapeutic target in CRC.https://doi.org/10.1002/1878-0261.12372CHIP E3 ligasecolorectal cancermortalin‐2mouseUBXN2Averatridine |
| spellingShingle | Sanam Sane Andre Hafner Rekha Srinivasan Daniall Masood John l. Slunecka Collin J. Noldner Alex D. Hanson Taylor Kruisselbrink Xuejun Wang Yiyang Wang Jun Yin Khosrow Rezvani UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells Molecular Oncology CHIP E3 ligase colorectal cancer mortalin‐2 mouse UBXN2A veratridine |
| title | UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells |
| title_full | UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells |
| title_fullStr | UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells |
| title_full_unstemmed | UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells |
| title_short | UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells |
| title_sort | ubxn2a enhances chip mediated proteasomal degradation of oncoprotein mortalin 2 in cancer cells |
| topic | CHIP E3 ligase colorectal cancer mortalin‐2 mouse UBXN2A veratridine |
| url | https://doi.org/10.1002/1878-0261.12372 |
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