The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression
Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxy...
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Elsevier
2024-12-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824004390 |
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| author | Xiuwei Mi Yudong Duan Jiying Sun Qingliang Tai Huihui Yao Lijun Meng Xiaoshan Yang Xinyu Shi Bo Shi Junjie Chen Liang Sun Diyuan Zhou Sheng Xiao Yizhou Yao Songbing He |
| author_facet | Xiuwei Mi Yudong Duan Jiying Sun Qingliang Tai Huihui Yao Lijun Meng Xiaoshan Yang Xinyu Shi Bo Shi Junjie Chen Liang Sun Diyuan Zhou Sheng Xiao Yizhou Yao Songbing He |
| author_sort | Xiuwei Mi |
| collection | DOAJ |
| description | Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils. |
| format | Article |
| id | doaj-art-9a1dff828c9140feb452fb7aca205abe |
| institution | DOAJ |
| issn | 1096-1186 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-9a1dff828c9140feb452fb7aca205abe2025-08-20T02:49:40ZengElsevierPharmacological Research1096-11862024-12-0121010749410.1016/j.phrs.2024.107494The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progressionXiuwei Mi0Yudong Duan1Jiying Sun2Qingliang Tai3Huihui Yao4Lijun Meng5Xiaoshan Yang6Xinyu Shi7Bo Shi8Junjie Chen9Liang Sun10Diyuan Zhou11Sheng Xiao12Yizhou Yao13Songbing He14Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Advanced Molecular Pathology Institute of Soochow University and SANO, & SANO Medical Laboratories Suzhou, Jiangsu 215000, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaAdvanced Molecular Pathology Institute of Soochow University and SANO, & SANO Medical Laboratories Suzhou, Jiangsu 215000, China; Department of Respiratory Diseases, Children's Hospital of Soochow University, Suzhou, Jiangsu 215025, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaAdvanced Molecular Pathology Institute of Soochow University and SANO, & SANO Medical Laboratories Suzhou, Jiangsu 215000, ChinaAdvanced Molecular Pathology Institute of Soochow University and SANO, & SANO Medical Laboratories Suzhou, Jiangsu 215000, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaDepartment of General Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215299, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaDepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, ChinaDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Corresponding authors.Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China; Corresponding authors.Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils.http://www.sciencedirect.com/science/article/pii/S1043661824004390Ketogenic dietβ-hydroxybutyrateNeutrophilsN1/N2 polarizationColorectal cancer |
| spellingShingle | Xiuwei Mi Yudong Duan Jiying Sun Qingliang Tai Huihui Yao Lijun Meng Xiaoshan Yang Xinyu Shi Bo Shi Junjie Chen Liang Sun Diyuan Zhou Sheng Xiao Yizhou Yao Songbing He The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression Pharmacological Research Ketogenic diet β-hydroxybutyrate Neutrophils N1/N2 polarization Colorectal cancer |
| title | The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression |
| title_full | The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression |
| title_fullStr | The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression |
| title_full_unstemmed | The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression |
| title_short | The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression |
| title_sort | ketogenic diet modulates tumor associated neutrophil polarization via the amot yap taz axis to inhibit colorectal cancer progression |
| topic | Ketogenic diet β-hydroxybutyrate Neutrophils N1/N2 polarization Colorectal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824004390 |
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