Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression
Abstract The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically in...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2023-03-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202215924 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846171737644859392 |
|---|---|
| author | Heng Zhang Gang Chen Xing Feng Huiwen Song Lingbing Meng Yao Fu Jun Yang Zhiwen Fan Youxiang Ding Zhijie Du Jianchao Wang Li Yang Jun Zhang Lixia Sun Zhigang Liu Zhiyong Zhang Quanhai Li Xiangshan Fan |
| author_facet | Heng Zhang Gang Chen Xing Feng Huiwen Song Lingbing Meng Yao Fu Jun Yang Zhiwen Fan Youxiang Ding Zhijie Du Jianchao Wang Li Yang Jun Zhang Lixia Sun Zhigang Liu Zhiyong Zhang Quanhai Li Xiangshan Fan |
| author_sort | Heng Zhang |
| collection | DOAJ |
| description | Abstract The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune‐competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A‐DDB1‐ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid‐derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF‐κB to activate the transcription of WDR6, establishing a WDR6‐TNFα loop. Clinically, the WDR6/UVRAG/NF‐κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR‐like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti‐PD‐L1 against HCC with WDR6 dysregulation. |
| format | Article |
| id | doaj-art-5bfd209afc0d41bdadd0c7bc9bb6f97a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-5bfd209afc0d41bdadd0c7bc9bb6f97a2024-11-10T12:37:39ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-03-0115511910.15252/emmm.202215924Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progressionHeng Zhang0Gang Chen1Xing Feng2Huiwen Song3Lingbing Meng4Yao Fu5Jun Yang6Zhiwen Fan7Youxiang Ding8Zhijie Du9Jianchao Wang10Li Yang11Jun Zhang12Lixia Sun13Zhigang Liu14Zhiyong Zhang15Quanhai Li16Xiangshan Fan17Department of Thoracic Surgery, Renmin Hospital of Wuhan UniversityDepartment of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer HospitalDepartment of Immunobiology, Yale University School of MedicineDepartment of Cardiology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health SciencesDepartments of Cardiology, Beijing Hospital, National Center of Gerontology, Chinese Academy of Medical SciencesDepartment of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical SchoolDepartment of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical SchoolDepartment of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical SchoolDepartment of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical SchoolNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineDepartment of Pathology, Fujian Medical University Cancer Hospital, Fujian Cancer HospitalInstitute of Digestive Disease, China Three Gorges UniversityShenzhen Qianhai Shekou Free Trade Zone HospitalDepartment of Hepatological Surgery, The Affiliated Wuhu hospital of ECNUDepartment of Hepatological Surgery, The Affiliated Wuhu hospital of ECNUDepartment of Surgery, Robert‐Wood‐Johnson Medical School University Hospital, Rutgers UniversityCell Therapy Laboratory, The First Hospital of Hebei Medical UniversityDepartment of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical SchoolAbstract The WD‐repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1‐6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune‐competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A‐DDB1‐ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid‐derived suppressor cell (MDSC) number, and reduces CD8+ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF‐κB to activate the transcription of WDR6, establishing a WDR6‐TNFα loop. Clinically, the WDR6/UVRAG/NF‐κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR‐like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti‐PD‐L1 against HCC with WDR6 dysregulation.https://doi.org/10.15252/emmm.202215924MDSCPD‐1TNFαUVRAGWDR6 |
| spellingShingle | Heng Zhang Gang Chen Xing Feng Huiwen Song Lingbing Meng Yao Fu Jun Yang Zhiwen Fan Youxiang Ding Zhijie Du Jianchao Wang Li Yang Jun Zhang Lixia Sun Zhigang Liu Zhiyong Zhang Quanhai Li Xiangshan Fan Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression EMBO Molecular Medicine MDSC PD‐1 TNFα UVRAG WDR6 |
| title | Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| title_full | Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| title_fullStr | Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| title_full_unstemmed | Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| title_short | Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| title_sort | targeting wdxr motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression |
| topic | MDSC PD‐1 TNFα UVRAG WDR6 |
| url | https://doi.org/10.15252/emmm.202215924 |
| work_keys_str_mv | AT hengzhang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT gangchen targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT xingfeng targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT huiwensong targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT lingbingmeng targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT yaofu targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT junyang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT zhiwenfan targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT youxiangding targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT zhijiedu targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT jianchaowang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT liyang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT junzhang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT lixiasun targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT zhigangliu targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT zhiyongzhang targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT quanhaili targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression AT xiangshanfan targetingwdxrmotifreprogramsimmunemicroenvironmentandinhibitshepatocellularcarcinomaprogression |