SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer
Authors: Hui Zhuang
Zihan Lin
Jie Zhu
Xiaofeng Jin
Zeheng Lv
Kun Gao
Qian Li
Ting Lin
Zhaohui Gong
Jian Wang
Liliang Shen
Chunhong Yan
Jingfei Zheng
Jianye Yang
Chenji Wang
Journal: American journal of cancer research (2019)
Discipline: CLINICAL MEDICINE
Keywords: SPOP; ZBTB3; endometrial cancer; sonic hedgehog; ubiquitination.
Affiliations: Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University Ningbo 315211, China., Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine Shanghai 200090, China., Department of Urology, Yinzhou Renmin Hospital Affiliated to Medical School of Ningbo University Ningbo 315040, China., Department of Obstetrics and Gynecology, Yinzhou Renmin Hospital Affiliated to Medical School of Ningbo University Ningbo 315040, China., Department of Hepato-Biliary-Pancreatic Surgery, The Affiliated Ningbo Medical Center of Lihuili Hospital of Medical School of Ningbo University Ningbo 315048, China., State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University Shanghai 200433, China.

Abstract:  Dysregulation of the ubiquitin-proteasome pathway is closely associated with cancer initiation and progression. SPOP is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. Several whole genome/exome sequencing studies on endometrial cancers (ECs) revealed that the SPOP gene is frequently mutated. However, how SPOP mutations contribute to EC remains poorly understood. In this study, transcription factor ZBTB3 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes two Ser/Thr (S/T)-rich degrons located in ZBTB3 and triggers the degradation of ZBTB3 via the ubiquitin-proteasome pathway. By contrast, EC-associated SPOP mutants are defective in regulating ZBTB3 stability. SPOP inactivation promotes endometrial cell proliferation, migration, and invasion partly through ZBTB3 accumulation. Sonic hedgehog (SHH) was found to be a transcriptional target of ZBTB3. SPOP inactivation leads to ZBTB3-dependent SHH upregulation in EC cells. RUSKI-43, a small molecule inhibitor of SHH, suppresses cell proliferation, migration, and invasion in SPOP-depleted or EC-associated SPOP mutant-overexpressed EC cells. Our data indicate that pharmacological inhibition of SHH represents a possible treatment strategy for SPOP-mutated ECs. 

Retracted: No

PubPeer comments:
 Figure five has a repeated image, despite being from two seemingly different experiments. ![file] , 
 #1 Thank you for your comment. We are so sorry for this careless error. This assay was repeated for 3 times. For comparison, we did this assay in the same cell culture plate(6 well) each time. Unfortunately, we selected the same vision when we published the-manuscript. The attachment below is the raw figure of colony formation in this assay. The figure labeled with red line was misused twice while the green one just nearby is correct, which will be used for the correction for our manuscript. Finally, we will contact the journal shortly for a correction for this figure, and we really appreciated your kindly and good comment on this manuscript.u00a0 ![file] , 
 #2 Dear Coronilla Vaginalis The Erratum: SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer. has already accepted by the American Journal of Cancer Research. [This corrects the article on p. 2797 in vol. 9, PMID: 31911863.]. ,