RCC2 promotes esophageal cancer growth by regulating activity and expression of the Sox2 transcription factor

Ali Calderon-Aparicio, Hiroyuki Yamamoto, Humberto de Vitto, Tianshun Zhang, Qiushi Wang, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

Abstract

Regulator of chromosome condensation 2 (RCC2) is a protein located in the centrosome, which ensures that cell division proceeds properly. Previous reports show that RCC2 is overexpressed in some cancers and could play a key role in tumor development, but the mechanisms concerning how this occurs are not understood. Furthermore, no evidence exists regarding its role in esophageal cancer. We studied the relevance of RCC2 in esophageal cancer growth and its regulation on Sox2, an important transcription factor promoting esophageal cancer. RCC2 was overexpressed in esophageal tumors compared with normal tissue, and this overexpression was associated with tumorigenicity by increasing cell proliferation, anchorage-independent growth, and migration. These oncogenic effects were accompanied by overexpression of Sox2. RCC2 upregulated and stabilized Sox2 expression and its target genes by inhibiting ubiquitination-mediated proteasome degradation. Likewise, RCC2 increased the transcriptional activity and promoter binding of Sox2. In vivo studies indicated that RCC2 and Sox2 were overexpressed in esophageal tumors compared with normal tissue, and this upregulation occurs in the esophageal basal cell layer for both proteins. In conditional knockout mice, RCC2 deletion decreased the tumor nodule formation and progression in the esophagus compared with wild-type mice. Proliferating cell nuclear antigen expression, a cell proliferation marker, was also downregulated in RCC2 knockout mice. Overall, our data show for the first time that RCC2 is an important protein for the stabilization and transcriptional activation of Sox2 and further promotion of malignancy in esophageal cancer. Implications: This study shows that RCC2 controls Sox2 expression and transcriptional activity to mediate esophageal cancer formation.

Original languageEnglish (US)
Pages (from-to)1660-1674
Number of pages15
JournalMolecular Cancer Research
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
The authors thank Tara Adams for assistance in handling the animal colonies. We also thank The Hormel Foundation for the financial support of this work.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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