title: Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis.
abstract: 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.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.|Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Xu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.|Department of Pathology, Chi-Mei Foundational Medical Center, Tainan 710, Taiwan.|Department of Biotechnology, Southern Taiwan University, Tainan 710, Taiwan.|Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.|Institute of Biochemistry and Molecular Biology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Szu-Wei
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Abdol-Hossein
authors.initials: AH
authors.lastname: Rezaeian
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Wei-Lei
authors.initials: WL
authors.lastname: Yang
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Feng
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.|Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.|School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Ying-Jan
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 110, Taiwan.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Chow
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Department of Gastric and Pancreatic Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: Department of Molecular and Cellular Oncology, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.|The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.|Department of Biotechnology, Asia University, Taichung 404, Taiwan.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005347:Fibroblasts; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D006657:Histones; D044786:S-Phase Kinase-Associated Proteins; C120756:macroH2A histone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044843:SKP Cullin F-Box Protein Ligases; C095686:CDK8 protein, human; C524803:Cdk8 protein, mouse; D056850:Cyclin-Dependent Kinase 8
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