USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration
Abstract Background Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targ...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-023-01441-5 |
| _version_ | 1797273855893438464 |
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| author | Evangelos Prokakis Husam Bamahmoud Shaishavi Jansari Lena Fritsche Alexander Dietz Angela Boshnakovska Peter Rehling Steven A. Johnsen Julia Gallwas Florian Wegwitz |
| author_facet | Evangelos Prokakis Husam Bamahmoud Shaishavi Jansari Lena Fritsche Alexander Dietz Angela Boshnakovska Peter Rehling Steven A. Johnsen Julia Gallwas Florian Wegwitz |
| author_sort | Evangelos Prokakis |
| collection | DOAJ |
| description | Abstract Background Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targets due to the particular enrichment of cancer stem cells (CSCs), frequently leading to a chemoresistant phenotype and metastasis. The Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase that has been frequently associated with a CSC-promoting function and intimately implicated in resistance to conventional therapies, tumor relapse, metastasis and overall poor survival in a broad range of cancer entities, including BC. To date, though, the role of USP22 in TNBC has been only superficially addressed. Methods The current study utilized the MMTV-cre, Usp22 fl/fl transgenic mouse model to study the involvement of USP22 in the stem cell-like properties of the growing mammary tissue. Additionally, we combined high-throughput transcriptomic analyses with publicly available patient transcriptomic data and utilized TNBC culture models to decipher the functional role of USP22 in the CSC characteristics of this disease. Results Interestingly, we identified that USP22 promotes CSC properties and drug tolerance by supporting the oxidative phosphorylation program, known to be largely responsible for the poor response to conventional therapies in this particularly aggressive BC subtype. Conclusions This study suggests a novel tumor-supportive role of USP22 in sustaining cellular respiration to facilitate the drug-tolerant behavior of HER2+-BC and TNBC cells. Therefore, we posit USP22 as a promising therapeutic target to optimize standard therapies and combat the aggressiveness of these malignancies. Video Abstract |
| first_indexed | 2024-03-07T14:50:07Z |
| format | Article |
| id | doaj.art-f99aa535c8c1441896abb3b0036937e9 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-07T14:50:07Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-f99aa535c8c1441896abb3b0036937e92024-03-05T19:47:28ZengBMCCell Communication and Signaling1478-811X2024-02-0122111710.1186/s12964-023-01441-5USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respirationEvangelos Prokakis0Husam Bamahmoud1Shaishavi Jansari2Lena Fritsche3Alexander Dietz4Angela Boshnakovska5Peter Rehling6Steven A. Johnsen7Julia Gallwas8Florian Wegwitz9Department of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenInstitute of Pathology, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of General, Visceral & Pediatric Surgery, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenDepartment of Gynecology and Obstetrics, University Medical Center GöttingenAbstract Background Breast cancer (BC) is the most frequent tumor entity in women worldwide with a high chance of therapeutic response in early- and non-metastatic disease stages. Among all BC subtypes, triple-negative BC (TNBC) is the most challenging cancer subtype lacking effective molecular targets due to the particular enrichment of cancer stem cells (CSCs), frequently leading to a chemoresistant phenotype and metastasis. The Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase that has been frequently associated with a CSC-promoting function and intimately implicated in resistance to conventional therapies, tumor relapse, metastasis and overall poor survival in a broad range of cancer entities, including BC. To date, though, the role of USP22 in TNBC has been only superficially addressed. Methods The current study utilized the MMTV-cre, Usp22 fl/fl transgenic mouse model to study the involvement of USP22 in the stem cell-like properties of the growing mammary tissue. Additionally, we combined high-throughput transcriptomic analyses with publicly available patient transcriptomic data and utilized TNBC culture models to decipher the functional role of USP22 in the CSC characteristics of this disease. Results Interestingly, we identified that USP22 promotes CSC properties and drug tolerance by supporting the oxidative phosphorylation program, known to be largely responsible for the poor response to conventional therapies in this particularly aggressive BC subtype. Conclusions This study suggests a novel tumor-supportive role of USP22 in sustaining cellular respiration to facilitate the drug-tolerant behavior of HER2+-BC and TNBC cells. Therefore, we posit USP22 as a promising therapeutic target to optimize standard therapies and combat the aggressiveness of these malignancies. Video Abstracthttps://doi.org/10.1186/s12964-023-01441-5Breast cancerTNBCEpigeneticsUSP22OXPHOSCSCs |
| spellingShingle | Evangelos Prokakis Husam Bamahmoud Shaishavi Jansari Lena Fritsche Alexander Dietz Angela Boshnakovska Peter Rehling Steven A. Johnsen Julia Gallwas Florian Wegwitz USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration Cell Communication and Signaling Breast cancer TNBC Epigenetics USP22 OXPHOS CSCs |
| title | USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration |
| title_full | USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration |
| title_fullStr | USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration |
| title_full_unstemmed | USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration |
| title_short | USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration |
| title_sort | usp22 supports the aggressive behavior of basal like breast cancer by stimulating cellular respiration |
| topic | Breast cancer TNBC Epigenetics USP22 OXPHOS CSCs |
| url | https://doi.org/10.1186/s12964-023-01441-5 |
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