Presentation Authors: Xiang Yan*, Nanjing , China, People's Republic of
Introduction: Urinary bladder cancer (UBC) is one of the most common malignancies in the world, with the characteristics of frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Hence, it is needed to develop new drugs to tackle down UBC.
Methods: Histone modifiers, which are frequently dysregulated in cancer development, are excellent drug targets for cancer treatment. Here, we found that G9a, one of the histone H3 methyltransferases, was overexpressed significantly in human UBC patients, using the expressiondata from public databases. In the TCGA Provisional dataset, the average expression level of G9a in primary UBC samples (n=408) was 1.6-fold as much as that in normal bladder samples (n=19; P < 0.001). Knockdown G9a by small interfering RNA decreased cell viability and induced apoptosis in human UBC cell lines. Thus, UNC0642, a small molecule inhibitor targeting G9a with high selectivity, low cytotoxicity, and excellent in vivo pharmacokinetic properties, was chosen to test the inhibitory effect on UBC cells.
Results: UNC0642 decreased the level of histone H3K9me2, the downstream target of G9a, and increase apoptosis of UBC cells in vitro in a dosedependent manner. UNC0642 exhibited similar inhibitory effects on the J82 xenografts, without the loss of body weight of mice. Targeting G9a in vivo reduced Ki67 expression and increase the level of cleaved Caspase 3 and BIM protein by immunohistochemistry and Western blot analysis, respectively.
Conclusions: Taken together, our data indicate that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.
Source of Funding: This research was supported by the National Natural Science Fund of China (Nos. 81772712, 81702569)