3090

HIC1

Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis. In this study, we investigated a role of HIC1 in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. Downregulation of HIC1 occurred in approximately 70% of primary ESCCs at both mRNA and protein level where it was associated significantly with vascular invasion, advanced clinical stage, lymph node metastasis, and poor disease free survival (DFS). The promoter methylation analyses suggested that loss of HIC1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of HIC1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, tumor formation and epithelial-mesenchymal transition (EMT). Our results decipher the mechanism through which HIC1 deficiency induce ESCC cells to undergo EMT and promote tumor progression and metastasis through activation of EphA2 signaling pathway. Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression. We identify a novel pathway that linking HIC1 downregulation to EphA2-inducing EMT in ESCC cells and may shed light on the development of novel anti-tumor therapeutics.

Metastatic disease is the leading cause of death due to prostate cancer (PCa). Although the hypermethylated in cancer 1 (HIC1) gene has been observed to be epigenetically modified in PCa, its intrinsic role and mechanism in PCa metastasis still remain uncertain. Here, we show that hypermethylation of the HIC1 promoter markedly reduces its suppressive function in metastatic PCa tissues as compared with primary and adjacent normal prostate tissues, and is associated with poor patient survival. PCas in cancer-prone mice homozygous for a prostate-targeted Hic1 conditional knockout showed stronger metastatic behaviour than those in heterozygous mice, as a result of epithelial-mesenchymal transition (EMT). Moreover, impairment of HIC1 expression in PCa cells induced their migration and metastasis through EMT, by enhancing expression of Slug and CXCR4, both of which are critical to PCa metastasis; the CXCL12-CXCR4 axis promotes EMT by activating the extracellular signal-regulated kinase (ERK) 1/2 pathway. Taken together, our results suggest that evaluation of HIC1-CXCR4-Slug signalling may provide a potential predictor for PCa aggressiveness. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.CI - Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.