Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis
Abstract Background Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood. Methods We utilized 23 p...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04611-8 |
| _version_ | 1797556851268648960 |
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| author | Yue Kong Yugeng Liu Xianzhe Li Menglan Rao Dawei Li Xiaolan Ruan Shanglin Li Zhenyou Jiang Qiang Zhang |
| author_facet | Yue Kong Yugeng Liu Xianzhe Li Menglan Rao Dawei Li Xiaolan Ruan Shanglin Li Zhenyou Jiang Qiang Zhang |
| author_sort | Yue Kong |
| collection | DOAJ |
| description | Abstract Background Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood. Methods We utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes. Results We identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes. Conclusions Overall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy. |
| first_indexed | 2024-03-10T17:08:48Z |
| format | Article |
| id | doaj.art-6f6591be4c3846eea1b992dfb142bc64 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-10T17:08:48Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-6f6591be4c3846eea1b992dfb142bc642023-11-20T10:43:48ZengBMCJournal of Translational Medicine1479-58762023-11-0121111910.1186/s12967-023-04611-8Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesisYue Kong0Yugeng Liu1Xianzhe Li2Menglan Rao3Dawei Li4Xiaolan Ruan5Shanglin Li6Zhenyou Jiang7Qiang Zhang8Department of Microbiology and Immunology, Basic Medicine College, Jinan UniversityShenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural SciencesDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan UniversityZhumadian Central Hospital, Huanghuai UniversityGuangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan UniversityDepartment of Microbiology and Immunology, Basic Medicine College, Jinan UniversityDepartment of Microbiology and Immunology, Basic Medicine College, Jinan UniversityMolecular Cancer Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen UniversityAbstract Background Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood. Methods We utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes. Results We identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes. Conclusions Overall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy.https://doi.org/10.1186/s12967-023-04611-8PalmitoylationCancerDNA methylationc-MycImmunotherapySmall molecular |
| spellingShingle | Yue Kong Yugeng Liu Xianzhe Li Menglan Rao Dawei Li Xiaolan Ruan Shanglin Li Zhenyou Jiang Qiang Zhang Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis Journal of Translational Medicine Palmitoylation Cancer DNA methylation c-Myc Immunotherapy Small molecular |
| title | Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| title_full | Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| title_fullStr | Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| title_full_unstemmed | Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| title_short | Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| title_sort | palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis |
| topic | Palmitoylation Cancer DNA methylation c-Myc Immunotherapy Small molecular |
| url | https://doi.org/10.1186/s12967-023-04611-8 |
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