Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease
Abstract The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-10-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-22295-w |
| _version_ | 1828140507826487296 |
|---|---|
| author | Daniel Roca-Lema Macarena Quiroga Vineeta Khare Andrea Díaz-Díaz Aida Barreiro-Alonso Andrea Rodríguez-Alonso Ángel Concha Gabriela Romay M. Esperanza Cerdán Christoph Gasche Angélica Figueroa |
| author_facet | Daniel Roca-Lema Macarena Quiroga Vineeta Khare Andrea Díaz-Díaz Aida Barreiro-Alonso Andrea Rodríguez-Alonso Ángel Concha Gabriela Romay M. Esperanza Cerdán Christoph Gasche Angélica Figueroa |
| author_sort | Daniel Roca-Lema |
| collection | DOAJ |
| description | Abstract The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease. |
| first_indexed | 2024-04-11T19:10:39Z |
| format | Article |
| id | doaj.art-58d34e961d5a459f9da045abe6c74ca8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T19:10:39Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-58d34e961d5a459f9da045abe6c74ca82022-12-22T04:07:37ZengNature PortfolioScientific Reports2045-23222022-10-0112111510.1038/s41598-022-22295-wRole of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel diseaseDaniel Roca-Lema0Macarena Quiroga1Vineeta Khare2Andrea Díaz-Díaz3Aida Barreiro-Alonso4Andrea Rodríguez-Alonso5Ángel Concha6Gabriela Romay7M. Esperanza Cerdán8Christoph Gasche9Angélica Figueroa10Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of ViennaEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer ResearchEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Pathology Department and A Coruña Biobank From INIBIC, CHUAC, Sergas, UDCEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)EXPRELA, Centro de Investigacións Científicas Avanzadas (CICA), Departamento de BioloxíaFacultade de Ciencias, Universidade da CoruñaDivision of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of ViennaEpithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC)Abstract The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.https://doi.org/10.1038/s41598-022-22295-w |
| spellingShingle | Daniel Roca-Lema Macarena Quiroga Vineeta Khare Andrea Díaz-Díaz Aida Barreiro-Alonso Andrea Rodríguez-Alonso Ángel Concha Gabriela Romay M. Esperanza Cerdán Christoph Gasche Angélica Figueroa Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease Scientific Reports |
| title | Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease |
| title_full | Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease |
| title_fullStr | Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease |
| title_full_unstemmed | Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease |
| title_short | Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease |
| title_sort | role of the e3 ubiquitin ligase hakai in intestinal inflammation and cancer bowel disease |
| url | https://doi.org/10.1038/s41598-022-22295-w |
| work_keys_str_mv | AT danielrocalema roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT macarenaquiroga roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT vineetakhare roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT andreadiazdiaz roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT aidabarreiroalonso roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT andrearodriguezalonso roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT angelconcha roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT gabrielaromay roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT mesperanzacerdan roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT christophgasche roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease AT angelicafigueroa roleofthee3ubiquitinligasehakaiinintestinalinflammationandcancerboweldisease |