机构：[1]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, SunYat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China[2]Department of Molecular and Cellular Oncology, M.D.Anderson Cancer Center,The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA[3]National Institute of Cancer Research, National Health Research Institutes,Tainan 704, Taiwan[4]Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan[5]Department of Biotechnology, Southern TaiwanUniversity, Tainan 710, Taiwan[6]Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan[7]Institute of Biochemistry andMolecular Biology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China[8]Department of Chinese Medicine, Chiayi Chang Gung MemorialHospital, Chiayi 613, Taiwan[9]School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan[10]GraduateInstitute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 110, Taiwan[11]The University of Texas Graduate Schoolof Biomedical Sciences at Houston, Houston, Texas 77030, USA[12]Graduate Institute of Basic Medical Science, China Medical University, Taichung 404,Taiwan[13]Department of Biotechnology, Asia University, Taichung 404, Taiwan[14]Department of Pharmacological Sciences, Stony BrookUniversity, Stony Brook, New York 11790, USA
Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.
基金：
CPRIT
grant, NIH RO1 grants, R. Lee Clark Award, the MD Anderson Prostate SPORE
Development Award (P50CA40388) and the MD Anderson prostate moonshot program
to H.-K.L.; the National Natural Sciences Foundation of China (81372569) to D.X.; and
the grant from the Department of Health in Taiwan (MOHW103-TD-B-111-05 and
DOH102-TD-M-111-102001) to C.-F.L.
第一作者机构：[1]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, SunYat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China[2]Department of Molecular and Cellular Oncology, M.D.Anderson Cancer Center,The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA
通讯作者：
通讯机构：[1]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, SunYat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China[2]Department of Molecular and Cellular Oncology, M.D.Anderson Cancer Center,The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA[11]The University of Texas Graduate Schoolof Biomedical Sciences at Houston, Houston, Texas 77030, USA[12]Graduate Institute of Basic Medical Science, China Medical University, Taichung 404,Taiwan[13]Department of Biotechnology, Asia University, Taichung 404, Taiwan
综合性期刊