MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target

• Published in: Oncogene 2017-02, Vol.36 (5), p.700-713
• Main Authors: Sheng, Y H, He, Y, Hasnain, S Z, Wang, R, Tong, H, Clarke, D T, Lourie, R, Oancea, I, Wong, K Y, Lumley, J W, Florin, T H, Sutton, P, Hooper, J D, McMillan, N A, McGuckin, M A
• Format: Article
• Language: English
• Subjects: 13; 13/89; 14/1; 631/337/505; 631/67/1504/1885; 631/80/82; 64/60; 82/29; 82/51; 96/31; Animals; Antigens, Surface - genetics; Antigens, Surface - metabolism; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Apoptosis - physiology; bcl-X Protein - biosynthesis; Cell Biology; Cell Line, Tumor; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Fluorouracil - pharmacology; Heterografts; HT29 Cells; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Targeted Therapy; NF-kappa B - metabolism; Oncology; Original; original-article; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Signal Transduction
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.241

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-X L . MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133 + CD44 + cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.