TGFβ promotes mesenchymal phenotype of pancreatic cancer cells, in part, through epigenetic activation of VAV1

• Published in: Oncogene Vol. 36; no. 16; pp. 2202 - 2214
• Main Authors: Huang, P-H, Lu, P-J, Ding, L-Y, Chu, P-C, Hsu, W-Y, Chen, C-S, Tsao, C-C, Chen, B-H, Lee, C-T, Shan, Y-S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2017; Nature Publishing Group
• Subjects: 13/51; 14/105; 14/19; 38/39; 38/47; 38/61; 631/67/1504/1713; 64/110; 692/53/2422; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Benzamides - therapeutic use; Cancer; Cell Biology; Cell Line, Tumor; CpG islands; Demethylation; Disease Progression; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA fingerprinting; DNA methylation; DNMT1 protein; Epigenesis, Genetic; Epigenetics; Gemcitabine; Gene Expression Regulation, Neoplastic; Homeostasis; Human Genetics; Humans; Internal Medicine; Localization; Medical prognosis; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Mice; Mice, Transgenic; Molecular modelling; Oncology; original-article; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Peripheral blood; Phenotypes; Promoter Regions, Genetic; Proto-Oncogene Proteins c-vav - genetics; Pyrazoles - therapeutic use; Radiation therapy; Smad4 protein; Smad4 Protein - metabolism; Therapeutic targets; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.378

The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant Kras G12D . Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KP fl/fl C mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.