Downregulation of <i>SAFB</i> Sustains the NF- <b>κ</b> B Pathway by Targeting <i>TAK1</i> during the Progression of Colorectal Cancer

Abstract

<b>Purpose:</b> To investigate the role and the underlying mechanism of scaffold attachment factor B (<i>SAFB</i>) in the progression of colorectal cancer (CRC).<b>Experimental Design:</b> SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of <i>SAFB</i> in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-β-activated kinase 1 (<i>TAK1</i>) and NF-κB signaling by <i>SAFB</i> The role of SAFB in invasion, metastasis, and angiogenesis was investigated using <i>in vitro</i> and <i>in vivo</i> assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.<b>Results:</b> SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-κB signaling by targeting the <i>TAK1</i> promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both <i>in vitro</i> and <i>in vivo</i> The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1- and NF-κB-related genes.<b>Conclusions:</b> Our results show that <i>SAFB</i> regulated the activity of NF-κB signaling in CRC by targeting <i>TAK1</i> This novel mechanism provides a comprehensive understanding of both SAFB and the NF-κB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-κB axis is a potential target for early therapeutic intervention in CRC progression. <i>Clin Cancer Res; 23(22); 7108-18. ©2017 AACR</i>.