title: Endometrial cancer-associated mutants of SPOP are defective in regulating estrogen receptor-α protein turnover.
abstract: Increasing amounts of evidence strongly suggests that dysregulation of ubiquitin-proteasome system is closely associated with cancer pathogenesis. Speckle-type POZ protein (SPOP) is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. It selectively recruits substrates for their ubiquitination and subsequent degradation. Recently, several exome-sequencing studies of endometrial cancer revealed high frequency somatic mutations in SPOP (5.7-10%). However, how SPOP mutations contribute to endometrial cancer remains unknown. Here, we identified estrogen receptor-α (ERα), a major endometrial cancer promoter, as a substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes multiple Ser/Thr (S/T)-rich degrons located in the AF2 domain of ERα, and triggers ERα degradation via the ubiquitin-proteasome pathway. SPOP depletion by siRNAs promotes endometrial cells growth. Strikingly, endometrial cancer-associated mutants of SPOP are defective in regulating ERα degradation and ubiquitination. Furthermore, we found that SPOP participates in estrogen-induced ERα degradation and transactivation. Our study revealed novel molecular mechanisms underlying the regulation of ERα protein homeostasis in physiological and pathological conditions, and provided insights in understanding the relationship between SPOP mutations and the development of endometrial cancer.
authors.affiliation: 1] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China [2] Shanghai Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: K
authors.initials: K
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: X
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: R
authors.initials: R
authors.lastname: Wumaier
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: J
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Pathology, The University of Arizona Medical Center, 1501N. Campbell Ave, Tucson, Arizona 85724, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: 1] State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China [2] Shanghai Cancer Center, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009687:Nuclear Proteins; C479529:RBX1 protein, human; D012097:Repressor Proteins; C509761:SPOP protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex