Overexpression of OTU domain-containing ubiquitin aldehyde-binding protein 1 exacerbates colorectal cancer malignancy by inhibiting protein degradation of β-Catenin via Ubiquitin-proteasome pathway

Abstract

ABSTRACT Although major advances were achieved in colorectal cancer (CRC) therapy, major concerns still remain on proper control of cancer metastasis and chemo-resistance in order to achieve satisfactory general treatment response. Previous studies suggested that OTUB1 (OTU domain-containing ubiquitin aldehyde-binding protein 1) serves as regulator of gene ubiquitination and participates in the pathogenesis of multiple malignancies. Therefore, to discover its molecular mechanism in CRC tumor growth and metastasis will contribute in CRC treatment strategy development. Clinical tissues and CRC cancer cell lines were utilized to evaluate OTUB1 expression pattern. Functional tests including cellular proliferation, migration and invasion, as well as chemo-resistance, etc., were evaluated to investigate the role of OTUB1/β-catenin regulatory pathway on CRC malignant biological behaviors. Both CRC tumor tissues and CRC cell lines exhibited promoted OTUB1 expression level. Subsequent experiments further suggested that OTUB1 promoted CRC malignancy by enhancing protein stability of β-catenin, via inhibition of its protein degradation by UPP pathway, which indicated its crucial role in enhancement of CRC tumor cellular proliferative and chemo-resistant capabilities. This study reported that OTUB1 exhibited novel pro-survival and pro-metastatic function by interaction of β-Catenin via Ubiquitin-proteasome pathway. Our research indicated that OTUB1/β-Catenin regulatory axis might be potential druggable target for CRC cancer patients’ treatment.