Upregulation of the oncoprotein SET determines poor clinical outcomes in hepatocellular carcinoma and shows therapeutic potential

• Published in: Oncogene 2016-09, Vol.35 (37), p.4891-4902
• Main Authors: Hung, M-H, Chen, Y-L, Chu, P-Y, Shih, C-T, Yu, H-C, Tai, W-T, Shiau, C-W, Chen, K-F
• Format: Article
• Language: English
• Subjects: 631/67/1059/602; 631/67/1504/1610; 631/67/395; AKT protein; Animals; Antagonists; Apoptosis; Apoptosis - drug effects; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Clinical outcomes; Development and progression; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Hepatocellular carcinoma; Histone Chaperones - antagonists & inhibitors; Histone Chaperones - genetics; Human Genetics; Humans; Innovations; Internal Medicine; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Mice; Molecular targeted therapy; Niacinamide - administration & dosage; Niacinamide - analogs & derivatives; Oncogenes; Oncology; Oncoproteins; original-article; Patient outcomes; Patients; Phenylurea Compounds - administration & dosage; Phosphoprotein phosphatase; Prognosis; Properties; Protein phosphatase; Proteins; Quinazolines - administration & dosage; Quinazolines - chemical synthesis; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.21

The SET protein is a potent inhibitor of protein phosphatase 2A (PP2A). Here, we report the oncogenic role of SET in hepatocarcinogenesis, clinical aggressiveness and anti-hepatocellular carcinoma (HCC) therapeutics. By analyzing samples obtained from 147 HCC patients, we found that SET overexpression was detected specifically in 30.6% HCC tumor samples, and was significantly associated with worse clinical features and high p-Akt expression in HCC tumors. Co-expression of SET and Akt predicted shorter post-operative recurrence-free survival in this cohort ( P =0.045). Furthermore, SET was significantly associated with cell growth and hepatosphere formation. To elucidate the anti-HCC potential of targeting SET, we generated a novel SET antagonist, EMQA (N 4 -(3-ethynylphenyl)-6,7-dimethoxy-N 2 -(4-phenoxyphenyl) quinazoline-2,4-diamine). EMQA enhanced PP2A activity via disrupting SET-PP2Ac (catalytic domain of PP2A) binding in HCC cells, which restored PP2A-mediated p-Akt downregulation and promoted HCC cell death. In HCC cells or recombinant proteins expressing the N- and C- truncated forms of SET, only the C-terminal SET was required for EMQA targeting. Furthermore, combining sorafenib and EMQA showed good synergism in inhibiting HCC survival. Our findings suggested the oncogenic role of SET and the adverse prognostic value of SET overexpression in HCC. This alteration defines a subgroup of HCC patients who could benefit from SET antagonists, such as EMQA.