Palmitoyl transferases act as novel drug targets for pancreatic cancer
Abstract Background Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the st...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04098-3 |
| _version_ | 1797845832843657216 |
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| author | Zhiqing Lin Ziru Lv Xin Liu Keke Huang |
| author_facet | Zhiqing Lin Ziru Lv Xin Liu Keke Huang |
| author_sort | Zhiqing Lin |
| collection | DOAJ |
| description | Abstract Background Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. Methods Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. Results ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. Conclusion This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer. |
| first_indexed | 2024-04-09T17:45:20Z |
| format | Article |
| id | doaj.art-bad12cc5220a4a49a0fb9f4344316b8c |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T17:45:20Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-bad12cc5220a4a49a0fb9f4344316b8c2023-04-16T11:23:47ZengBMCJournal of Translational Medicine1479-58762023-04-0121112410.1186/s12967-023-04098-3Palmitoyl transferases act as novel drug targets for pancreatic cancerZhiqing Lin0Ziru Lv1Xin Liu2Keke Huang3Department of Ophthalmology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong UniversitySchool of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversitySchool of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical UniversityDepartment of Ophthalmology, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong UniversityAbstract Background Pancreatic adenocarcinoma (PAAD) is one of the most leading causes of cancer-related death across the world with the limited efficiency and response rate of immunotherapy. Protein S-palmitoylation, a powerful post-translational lipid modification, is well-known to regulate the stability and cellular distribution of cancer-related proteins, which is mediated by a family of 23 palmitoyl transferases, namely zinc finger Asp-His-His-Cys-type (ZDHHC). However, whether palmitoyl transferases can determine tumor progression and the efficacy of immunotherapy in PAAD remains unknown. Methods Bioinformatics methods were used to identify differential ZDHHCs expression in PAAD. A systematic pan-cancer analysis was conducted to assess the immunological role of ZDHHC3 using RNA sequencing data from The Cancer Genome Atlas database. In vivo Panc 02 subcutaneous tumor model validated the anti-tumor effect of knockdown of ZDHHC3 or intraperitoneal injection of 2-bromopalmitate (2-BP), a typical broad-spectrum palmitoyl transferases inhibitor. Furthermore, we explored therapeutic strategies with combinations of 2-BP with PD-1/PD-L1-targeted immunotherapy in C57BL/6 mice bearing syngeneic Panc 02 pancreatic tumors. Results ZDHHC enzymes were associated with distinct prognostic values of pancreatic cancer. We identified that ZDHHC3 expression promotes an immunosuppressive tumor microenvironment in PAAD. 2-BP suppressed pancreatic-tumor cell viability and tumor sphere-forming activities, as well as increased cell apoptosis in vitro, without affecting normal human pancreatic ductal epithelial cells. Furthermore, genetic inactivation of ZDHHC3 or intraperitoneal injection of 2-BP impeded tumor progression in Panc 02 pancreatic tumors with enhanced anti-tumor immunity. 2-BP treatment significantly enhanced the therapeutic efficacy of PD-1/PD-L1 inhibitors in Panc 02 pancreatic tumors. Conclusion This study revealed some ZDHHC enzyme genes for predicting the prognosis of pancreatic cancer, and demonstrated that ZDHHC3 plays a critical oncogenic role in pancreatic cancer progression, highlighting its potential as an immunotherapeutic target of pancreatic cancer. In addition, combination therapy of 2-BP and PD-1/PD-L1 achieved synergic therapy effects in a mouse model of pancreatic cancer.https://doi.org/10.1186/s12967-023-04098-3Pancreatic adenocarcinomaZDHHC enzymesZDHHC3Immunotherapy |
| spellingShingle | Zhiqing Lin Ziru Lv Xin Liu Keke Huang Palmitoyl transferases act as novel drug targets for pancreatic cancer Journal of Translational Medicine Pancreatic adenocarcinoma ZDHHC enzymes ZDHHC3 Immunotherapy |
| title | Palmitoyl transferases act as novel drug targets for pancreatic cancer |
| title_full | Palmitoyl transferases act as novel drug targets for pancreatic cancer |
| title_fullStr | Palmitoyl transferases act as novel drug targets for pancreatic cancer |
| title_full_unstemmed | Palmitoyl transferases act as novel drug targets for pancreatic cancer |
| title_short | Palmitoyl transferases act as novel drug targets for pancreatic cancer |
| title_sort | palmitoyl transferases act as novel drug targets for pancreatic cancer |
| topic | Pancreatic adenocarcinoma ZDHHC enzymes ZDHHC3 Immunotherapy |
| url | https://doi.org/10.1186/s12967-023-04098-3 |
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