Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers
The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/111198 https://orcid.org/0000-0002-2988-0537 https://orcid.org/0000-0003-1533-6730 https://orcid.org/0000-0002-9703-1780 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1826196491733041152 |
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| author | Tsvetkov, Peter Brune, Zarina Thiru, Prathapan Ghandi, Mahmoud Santagata, Sandro Whitesell, Luke Sokol, Ethan Samuel Jin, Dexter X. Gupta, Piyush Lindquist, Susan Garraway, Levi A. |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Tsvetkov, Peter Brune, Zarina Thiru, Prathapan Ghandi, Mahmoud Santagata, Sandro Whitesell, Luke Sokol, Ethan Samuel Jin, Dexter X. Gupta, Piyush Lindquist, Susan Garraway, Levi A. |
| author_sort | Tsvetkov, Peter |
| collection | MIT |
| description | The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers. |
| first_indexed | 2024-09-23T10:27:48Z |
| format | Article |
| id | mit-1721.1/111198 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:27:48Z |
| publishDate | 2017 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1111982022-09-30T21:19:06Z Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers Tsvetkov, Peter Brune, Zarina Thiru, Prathapan Ghandi, Mahmoud Santagata, Sandro Whitesell, Luke Sokol, Ethan Samuel Jin, Dexter X. Gupta, Piyush Lindquist, Susan Garraway, Levi A. Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Sokol, Ethan Samuel Jin, Dexter X. Garraway, Levi Gupta, Piyush Lindquist, Susan The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers. 2017-09-13T19:30:56Z 2017-09-13T19:30:56Z 2016-12 2016-11 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/111198 Tsvetkov, Peter et al. “Suppression of 19S Proteasome Subunits Marks Emergence of an Altered Cell State in Diverse Cancers.” Proceedings of the National Academy of Sciences 114, 2 (Janaury 2017): 382–387 © 2017 National Academy of Sciences https://orcid.org/0000-0002-2988-0537 https://orcid.org/0000-0003-1533-6730 https://orcid.org/0000-0002-9703-1780 https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1073/pnas.1619067114 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Tsvetkov, Peter Brune, Zarina Thiru, Prathapan Ghandi, Mahmoud Santagata, Sandro Whitesell, Luke Sokol, Ethan Samuel Jin, Dexter X. Gupta, Piyush Lindquist, Susan Garraway, Levi A. Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title | Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title_full | Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title_fullStr | Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title_full_unstemmed | Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title_short | Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers |
| title_sort | suppression of 19s proteasome subunits marks emergence of an altered cell state in diverse cancers |
| url | http://hdl.handle.net/1721.1/111198 https://orcid.org/0000-0002-2988-0537 https://orcid.org/0000-0003-1533-6730 https://orcid.org/0000-0002-9703-1780 https://orcid.org/0000-0003-1307-882X |
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