Adenovirus-Mediated Delivery of Decoy Hyper Binding Sites Targeting Oncogenic HMGA1 Reduces Pancreatic and Liver Cancer Cell Viability

• Published in: Molecular therapy. Oncolytics Vol. 8; pp. 52 - 61
• Main Authors: Hassan, Faizule, Ni, Shuisong, Arnett, Tyler C., McKell, Melanie C., Kennedy, Michael A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-03-2018; Elsevier Limited; American Society of Gene & Cell Therapy; Elsevier
• Subjects: adenovirus; Adenoviruses; Apoptosis; Binding sites; Cancer therapies; cancer therapy; Cell growth; Cell proliferation; Cell viability; Chemoresistance; Chemotherapy; chemotherapy resistance; Cyclin-dependent kinases; decoy binding site; Deoxyribonucleic acid; DNA; DNA repair; Gemcitabine; Gene expression; Genomes; Hepatocytes; high mobility group A protein; High mobility group proteins; HMGA1; Infections; Kinases; Liver cancer; MicroRNAs; neoadjuvant therapy; oncogenic transcription factor; Pancreas; Pancreatic cancer; Proteins; Replication; Transcription factors; Tumor cell lines; cancer therapy; chemotherapy resistance; pancreatic cancer; adenovirus; HMGA1; decoy binding site; high mobility group A protein; liver cancer; oncogenic transcription factor; neoadjuvant therapy
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2018.01.002

High mobility group AT-hook 1 (HMGA1) protein is an oncogenic architectural transcription factor that plays an essential role in early development, but it is also implicated in many human cancers. Elevated levels of HMGA1 in cancer cells cause misregulation of gene expression and are associated with increased cancer cell proliferation and increased chemotherapy resistance. We have devised a strategy of using engineered viruses to deliver decoy hyper binding sites for HMGA1 to the nucleus of cancer cells with the goal of sequestering excess HMGA1 at the decoy hyper binding sites due to binding competition. Sequestration of excess HMGA1 at the decoy binding sites is intended to reduce HMGA1 binding at the naturally occurring genomic HMGA1 binding sites, which should result in normalized gene expression and restored sensitivity to chemotherapy. As proof of principle, we engineered the replication defective adenovirus serotype 5 genome to contain hyper binding sites for HMGA1 composed of six copies of an individual HMGA1 binding site, referred to as HMGA-6. A 70%–80% reduction in cell viability and increased sensitivity to gemcitabine was observed in five different pancreatic and liver cancer cell lines 72 hr after infection with replication defective engineered adenovirus serotype 5 virus containing the HMGA-6 decoy hyper binding sites. The decoy hyper binding site strategy should be general for targeting overexpression of any double-stranded DNA-binding oncogenic transcription factor responsible for cancer cell proliferation.
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