GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer
Abstract Background Advanced prostate cancer (PCa) often initially responds to androgen receptor signaling inhibitors (ARSI) but frequently develops resistance, driven by tumor heterogeneity and therapeutic pressure. Addressing the clinical challenge of identifying non-responsive patients and discov...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01977-0 |
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| author | Chuanfan Zhong Jiaxing Wang Hangyang Peng Jianming Lu Zining Long Zhuoyuan Lin Guo Chen Chao Cai Shilong Cheng Zhongjie Chen Le Zhang Weibo Zhong Rujun Mo Xiangming Mao |
| author_facet | Chuanfan Zhong Jiaxing Wang Hangyang Peng Jianming Lu Zining Long Zhuoyuan Lin Guo Chen Chao Cai Shilong Cheng Zhongjie Chen Le Zhang Weibo Zhong Rujun Mo Xiangming Mao |
| author_sort | Chuanfan Zhong |
| collection | DOAJ |
| description | Abstract Background Advanced prostate cancer (PCa) often initially responds to androgen receptor signaling inhibitors (ARSI) but frequently develops resistance, driven by tumor heterogeneity and therapeutic pressure. Addressing the clinical challenge of identifying non-responsive patients and discovering new therapeutic targets is urgently needed. Methods We utilized single-sample gene set enrichment analysis (ssGSEA) to elucidate the influence of the GG-NER pathway on ARSI response in PCa. We then constructed and validated a prognostic model based on this pathway using LASSO regression, Kaplan-Meier analysis, Cox regression, and ROC analysis. Additionally, we mapped tumor mutations to delineate the mutational landscapes across different risk groups and explored functional pathways through GO, KEGG, and GSEA analyses. The impact of the GG-NER pathway on enzalutamide sensitivity and DNA repair in PCa was further validated through CCK-8 assays, colony formation assays, in vivo experiments, and immunofluorescence. Results ssGSEA indicated a trend of GG-NER pathway upregulation in patients with poor ARSI response. The GG-NER characteristic gene score (NECGS) identified a high-risk group with diminished ARSI response, serving as an independent prognostic indicator with strong predictive power. This high-risk group exhibited elevated TP53 mutation frequencies and significant enrichment in key pathways such as ribosome and mitochondrial functions, as well as MYC and E2F signaling. Experimental validation confirmed that targeting the GG-NER pathway or its key gene, ACTL6A, significantly reduces enzalutamide resistance in resistant cell lines and increases γH2AX expression. Conclusion NECGS effectively predicts ARSI response in PCa, and our comprehensive analysis underscores the critical role of the GG-NER pathway in enzalutamide resistance, positioning ACTL6A as a potential therapeutic target for PCa. |
| format | Article |
| id | doaj-art-d5e7cf6ca664473683d7518a54ec0d66 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-d5e7cf6ca664473683d7518a54ec0d662024-12-22T12:37:44ZengBMCCell Communication and Signaling1478-811X2024-12-0122111710.1186/s12964-024-01977-0GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancerChuanfan Zhong0Jiaxing Wang1Hangyang Peng2Jianming Lu3Zining Long4Zhuoyuan Lin5Guo Chen6Chao Cai7Shilong Cheng8Zhongjie Chen9Le Zhang10Weibo Zhong11Rujun Mo12Xiangming Mao13Department of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Andrology, Guangzhou First People’s Hospital, Guangzhou Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical UniversityDepartment of Urology, The First Affiliated Hospital of Jinan UniversityDepartment of Urology, Minimally Invasive Surgery Center, Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityInstitute for Integrative Genome Biology, University of CaliforniaDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, The Tenth Affiliated Hospital of Southern Medical University (Dongguan people’s hospital)Department of Urology, Zhujiang Hospital, Southern Medical UniversityAbstract Background Advanced prostate cancer (PCa) often initially responds to androgen receptor signaling inhibitors (ARSI) but frequently develops resistance, driven by tumor heterogeneity and therapeutic pressure. Addressing the clinical challenge of identifying non-responsive patients and discovering new therapeutic targets is urgently needed. Methods We utilized single-sample gene set enrichment analysis (ssGSEA) to elucidate the influence of the GG-NER pathway on ARSI response in PCa. We then constructed and validated a prognostic model based on this pathway using LASSO regression, Kaplan-Meier analysis, Cox regression, and ROC analysis. Additionally, we mapped tumor mutations to delineate the mutational landscapes across different risk groups and explored functional pathways through GO, KEGG, and GSEA analyses. The impact of the GG-NER pathway on enzalutamide sensitivity and DNA repair in PCa was further validated through CCK-8 assays, colony formation assays, in vivo experiments, and immunofluorescence. Results ssGSEA indicated a trend of GG-NER pathway upregulation in patients with poor ARSI response. The GG-NER characteristic gene score (NECGS) identified a high-risk group with diminished ARSI response, serving as an independent prognostic indicator with strong predictive power. This high-risk group exhibited elevated TP53 mutation frequencies and significant enrichment in key pathways such as ribosome and mitochondrial functions, as well as MYC and E2F signaling. Experimental validation confirmed that targeting the GG-NER pathway or its key gene, ACTL6A, significantly reduces enzalutamide resistance in resistant cell lines and increases γH2AX expression. Conclusion NECGS effectively predicts ARSI response in PCa, and our comprehensive analysis underscores the critical role of the GG-NER pathway in enzalutamide resistance, positioning ACTL6A as a potential therapeutic target for PCa.https://doi.org/10.1186/s12964-024-01977-0GG-NERProstate cancerARSIACTL6AEnzalutamide |
| spellingShingle | Chuanfan Zhong Jiaxing Wang Hangyang Peng Jianming Lu Zining Long Zhuoyuan Lin Guo Chen Chao Cai Shilong Cheng Zhongjie Chen Le Zhang Weibo Zhong Rujun Mo Xiangming Mao GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer Cell Communication and Signaling GG-NER Prostate cancer ARSI ACTL6A Enzalutamide |
| title | GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| title_full | GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| title_fullStr | GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| title_full_unstemmed | GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| title_short | GG-NER’s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| title_sort | gg ner s role in androgen receptor signaling inhibitor response for advanced prostate cancer |
| topic | GG-NER Prostate cancer ARSI ACTL6A Enzalutamide |
| url | https://doi.org/10.1186/s12964-024-01977-0 |
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