PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells

• Published in: British journal of cancer 2013-10, Vol.109 (7), p.1795-1804
• Main Authors: Chien, W, Lee, K L, Ding, L W, Wuensche, P, Kato, H, Doan, N B, Poellinger, L, Said, J W, Koeffler, H P
• Format: Article
• Language: English
• Subjects: 631/80/86; 692/420/755; 692/699/67/1504/1713; Adenocarcinoma - metabolism; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Drug Resistance; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Jumonji Domain-Containing Histone Demethylases - biosynthesis; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Poly-ADP-Ribose Binding Proteins; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor - biosynthesis; Sumoylation; Tumors; Vascular Endothelial Growth Factor A - biosynthesis; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.531

Background: The PIAS4 protein belongs to the family of protein inhibitors of activated STAT, but has since been implicated in various biological activities including the post-translational modification known as sumoylation. In this study, we explored the roles of PIAS4 in pancreatic tumourigenesis. Methods: The expression levels of PIAS4 in pancreatic cancer cells were examined. Cell proliferation and invasion was studied after overexpression and gene silencing of PIAS4. The effect of PIAS4 on hypoxia signalling was investigated. Results: The protein was overexpressed in pancreatic cancer cells compared with the normal pancreas. Gene silencing by PIAS4 small interfering RNA (siRNA) suppressed pancreatic cancer cell growth and overexpression of PIAS4 induced expression of genes related to cell growth. The overexpression of PIAS4 is essential for the regulation of the hypoxia signalling pathway. PIAS4 interacts with the tumour suppressor von Hippel-Lindau (VHL) and leads to VHL sumoylation, oligomerization, and impaired function. Pancreatic cancer cells (Panc0327, MiaPaCa2) treated with PIAS4 siRNA suppressed expression of the hypoxia-inducible factor hypoxia-inducible factor 1 alpha and its target genes JMJD1A, VEGF, and STAT3. Conclusion: Our study elucidates the role of PIAS4 in the regulation of pancreatic cancer cell growth, where the suppression of its activity represents a novel therapeutic target for pancreatic cancers.