Aberrant MCM10 SUMOylation induces genomic instability mediated by a genetic variant associated with survival of esophageal squamous cell carcinoma
Authors: Rong Zhong
Xiaoping Miao
Tianyi Dong
Jianbo Tian
Lu Wang
Zhihua Wang
Yimin Cai
Pingting Ying
Ying Zhu
Zequn Lu
Ming Zhang
Siyuan Niu
Jiang Chang
Shanshan Zhang
Journal: Clinical and Translational Medicine (2021)
Discipline: CLINICAL MEDICINE
Keywords: ESCC; MCM10; SUMOylation; genomic instability; survival.
Affiliations: Department of Epidemiology and Biostatistics Key Laboratory for Environment and Health School of Public Health Tongji Medical College Huazhong University of Sciences and Technology  Wuhan China, Department of Urology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China

Abstract:  Background: Esophageal squamous cell carcinoma (ESCC) is one of the common gastrointestinal malignancy with an inferior prognosis outcome. DNA replication licensing aberration induced by dysregulation of minichromosome maintenance proteins (MCMs) causes genomic instability and cancer metastasis. SUMOylation modification plays a pivotal role in regulation of genomic integrity, while its dysregulation fueled by preexisting germline variants in cancers remains poorly understood. Methods: Firstly, we conducted two-stage survival analysis consisting of an exome-wide association study in 904 ESCC samples and another independent 503 ESCC samples. Then, multipronged functional experiments were performed to illuminate the potential biological mechanisms underlying the promising variants, and MCM10 influences the ESCC progression. Finally, we tested the effects of MCM10 inhibitors on ESCC cells. Results: A germline variant rs2274110 located at the exon 15 of MCM10 was identified to be significantly associated with the prognosis of ESCC patients. Individuals carrying rs2274110-AA genotypes confer a poor survival (hazard ratio = 1.61, 95% confidence interval = 1.35-1.93, p = 1.35 √ó 10-7 ), compared with subjects carrying rs2274110-AG/GG genotypes. Furthermore, we interestingly found that the variant can increase SUMOylation levels at K669 site (Lys[K]699Arg[R]) of MCM10 protein mediated by SUMO2/3 enzymes, which resulted in an aberrant overexpression of MCM10. Mechanistically, aberrant overexpression of MCM10 facilitated the proliferation and metastasis abilities of ESCC cells in vitro and in vivo by inducing DNA over-replication and genomic instability, providing functional evidence to support our population finding that high expression of MCM10 is extensively presented in tumor tissues of ESCC and correlated with inferior survival outcomes of multiple cancer types, including ESCC. Finally, MCM10 inhibitors Suramin and its analogues were revealed to effectively block the metastasis of ESCC cells. Conclusions: These findings not only demonstrate a potential biological mechanism between aberrant SUMOylation, genomic instability and cancer metastasis, but also provide a promising biomarker aiding in stratifying ESCC individuals with different prognosis, as well as a potential therapeutic target MCM10. 

Retracted: No

PubPeer comments:
 An image in Figure 4C overlaps with another image in Figure 4D, represented in different groups.  , 
 Dear Phyllanthus concolor, during figure preparation, we inadvertently placed the transwell image of KYSE30-shMCM10-2 group in Figure 4D using KYSE30-MCM10[A] group. Here is the original image of KYSE30-shMCM10-2 group in Figure 4D as below. Thanks for pointing out this error. We have contacted the journal to correct it. ,