TET1 promotes malignant progression of cholangiocarcinoma with IDH1 wild‐type

Cholangiocarcinoma (CCA) is a highly lethal disease without effective therapeutic approaches. The whole genome sequencing data indicated that there are about 20% of CCA patients having IDH1 mutations which have been suggested to target 2-oxoglutarate (OG) dependent dioxygenases in promoting CCA carcinogenesis. However, the clinical study indicates that the CCA patients with mutant IDH1 have better prognosis than those with wild-type IDH1, further complicating the roles of 2-OG-dependent enzymes. This study aimed to clarify if TET1, which is one of the 2-OG dependent enzymes functioning in regulating 5-hydroxymethylcytosine (5hmC) formation, is involved in CCA progression. By analyzing the Cancer Genome Atlas (TCGA) dataset, TET1 mRNA was found to be substantially up-regulated in CCA patients when compared with non-cancerous bile ducts. Additionally, TET1 protein expression was significantly elevated in human CCA tumors as well. CCA cells were challenged with α-ketoglutarate (α-KG) and dimethyl-α-KG (DM-α-KG) which are co-substrates for TET1 dioxygenase. The treatments of α-KG and DM-α-KG promoted 5hmC formation and malignancy of CCA cells. Molecular and pharmacological approaches were used to inhibit TET1 activity and these treatments substantially suppressed 5hmC and CCA carcinogenesis. Mechanistically, it was found that knockdown of TET1 may suppress CCA progression by targeting cell growth and apoptosis through epigenetic regulation. Consistently, targeting TET1 significantly inhibited CCA malignant progression in a liver orthotopic xenograft model via targeting cell growth and apoptosis. In conclusion, our data suggests that expression of TET1 is highly associated with CCA carcinogenesis. It will be important to evaluate the TET1 expression in CCA tumors before the application of IDH1 mutation inhibitor, since the inhibitor suppresses 2-HG expression which may result in activation of TET, potentially leading to CCA malignancy.