SOX6 represses tumor growth of clear cell renal cell carcinoma by HMG domain-dependent regulation of Wnt/β-catenin signaling.

Abstract

Sex-determining region Y box (SOXs) are expressed in various cells and control cell fate and differentiation in a multitude of physiologic processes. SOX6, a main representative of SOXs, is involved in the regulation of carcinogenesis in various human malignancies. However, the role of SOX6 in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, SOX6 expression in ccRCC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism of SOX6 in ccRCC. We confirmed that SOX6 was frequently downregulated in ccRCC tissues and cell lines. Besides, downregulation of SOX6 was significantly associated with larger tumor sizes, advanced tumor stage, higher Fuhrman grades, and its expression could act as an independent prognostic factor for ccRCC (hazards ratio = 0.590, P = .026). Gain/loss-of-function experiments demonstrated that SOX6 could remarkably inhibit tumor cell growth and foci formation in vitro and xenograft tumorigenesis in vivo, respectively. Mechanistically, SOX6 could influence cell cycle by regulating the G1/the S phase transition and had an inhibitory effect on Wnt/β-catenin signaling as well as its target genes, c-Myc and cyclin D1. Interesting, the tumor-suppressive function of SOX6 was proved to be dependent on its specific high-mobility-group (HMG) domain. In general, our findings indicated that SOX6 was a novel tumor suppressor and prognostic biomarker in ccRCC. SOX6 could inhibit tumor growth by negatively regulating the Wnt/β-catenin signaling pathway in an HMG domain-dependent manner in ccRCC, which might provide a novel therapeutic approach for ccRCC.

• Authors: Luyao Chen, Yongpeng Xie, Xin Ma, Yu Zhang, Xintao Li, Fan Zhang, Yu Gao, Yang Fan, Liangyou Gu, Lei Wang, Xu Zhang, Bin Fu
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 59 Issue 10 Pg. 1159-1173 (10 2020) ISSN: 1098-2744 [Electronic] United States
• PMID: 32794610 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Biomarkers, Tumor
• CTNNB1 protein, human
• SOX6 protein, human
• SOXD Transcription Factors
• WNT1 protein, human
• Wnt1 Protein
• beta Catenin

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Proliferation
• Cell Transformation, Neoplastic
• Female
• Gene Expression Regulation, Neoplastic
• HMG-Box Domains
• Humans
• Kidney Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Prognosis
• SOXD Transcription Factors (genetics, metabolism)
• Survival Rate
• Tumor Cells, Cultured
• Wnt1 Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays
• beta Catenin (genetics, metabolism)