Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma

Abstract

In human cancers, giant cadherin FAT1 may function both, as an oncogene and a tumor suppressor. Here, we investigated the expression and function of FAT1 in hepatocellular carcinoma (HCC). FAT1 expression was increased in human HCC cell lines and tissues compared with primary human hepatocytes and non-tumorous liver tissue as assessed by quantitative PCR and western blot analysis. Combined immunohistochemical and tissue microarray analysis showed a significant correlation of FAT1 expression with tumor stage and proliferation. Suppression of FAT1 expression by short hairpin RNA impaired proliferation and migration as well as apoptosis resistance of HCC cells in vitro. In nude mice, tumors formed by FAT1-suppressed HCC cells showed a delayed onset and more apoptosis compared with tumors of control cells. Both hepatocyte growth factor and hypoxia-mediated hypoxia-inducible factor 1 alpha activation were identified as strong inducers of FAT1 in HCC. Moreover, demethylating agents induced FAT1 expression in HCC cells. Hypoxia lead to reduced levels of the methyl group donor S-adenosyl-L-methionine (SAM) and hypoxia-induced FAT1 expression was inhibited by SAM supplementation in HCC cells. Together, these findings indicate that FAT1 expression in HCC is regulated via promotor methylation. FAT1 appears as relevant mediator of hypoxia and growth receptor signaling to critical tumorigenic pathways in HCC. This knowledge may facilitate the rational design of novel therapeutics against this highly aggressive malignancy.

FAT1 is a novel upstream regulator of HIF1α and invasion of high grade glioma

“…Negative expression of FAT1 has been correlated to gene deletion and promoter hypermethylation in oral cancer . A study in hepatocellular carcinoma by Valletta et al . have shown increased FAT1 expression under hypoxia and linked that to increased HGF (hepatocellular growth factor) and hypoxia related altered promoter methylation status.…”

“…FAT1 regulates the invasive and/or migratory potential of the normal and cancer cells . FAT1 exhibits a dual role as it could act as an oncogene or tumour suppressor in different tumour types. For the first time, our laboratory had demonstrated a role of FAT1 in GBM .…”

“…The underlying mechanism includes stimulation of AP1‐mediated transcriptional activation due to the down‐regulation of the tumour suppressor gene, PDCD4 . More recently, increased FAT1 expression has been noted in hepatocellular carcinoma due to reduced levels of the methyl group donor S‐adenosyl‐ l ‐methionine under hypoxia …”

Immunohistochemical localization of a proto‐cadherin fat tumour‐suppressor homolog in the regenerating tail of lizard suggests a role in apical growth control

“…Most studies have detected FAT proto‐cadherins in the normal epidermis and in squamous cell carcinomas (Horne‐Badovinac, ; Matsui et al, ; Nishikawa et al, ). Although these studies indicate that cancer is associated with the decrease in proto‐cadherin and FAT proteins in the tissues or to their inactivation by mutation, others studies have instead indicated that some proto‐cadherins actually increase and favour metastasis (Katoh, ; Lin et al, ; Valletta et al, ), as in in gastric tumour (Lin et al, ).…”

History and progression of Fat cadherins in health and disease

“…Furthermore, hypermethylation of CpG islands represents malignant progression. Thus, the methylation of Fat4 may be regarded as a potential epigenetic “driver” event for the development of tumors, rather than just a “passenger” event that would be without functional sequences 31. Moreover, Fat4 was silenced by methylation at CpG islands and was associated with infection by Helicobacter pylori in gastric cancer.…”