Uveal melanoma (UM) is a rare form of melanoma but is the most common intraocular cancer in adults. While primary tumours could be effectively treated with surgical or radiation procedures, ~50% of UM patients progress to metastatic disease where treatment options are limited. The survival rate for metastatic UM has remained poor over nearly four decades reveals the urgent needs to address the treatment resistance and metastatic progression in UM (1-3). Our previous work suggested that epigenetic drugs could enhance tumour suppressor gene expression and drug sensitivity in various cancer cell lines and animal models (4-6). Notably, histone methyltransferase EHMT2 (G9a) is found to be overexpressed in 54% of UM (TCGA data) and pathway analysis revealed that EHMT2 is responsible for silencing gene expression that promote apoptosis and cell death. A panel of UM cell lines derived from primary and metastatic UM were treated with small molecule inhibitor UNC0642 modulating EHMT2. The therapeutic efficacy of UNC0642 was further evaluated in xenograft UM tumour models. Our results demonstrated that EHMT2 inhibitor treatment effectively induced endoplasmic reticulum (ER) stress, attenuated survival of UM cell lines carrying GNAQ/11 mutations (present in approximately 75-85% of all UM) in vitro and resulted in a greater than four-fold reduction in tumour volume without apparent adverse events on mice. Thus, EHMT2 presents itself as a promising therapeutic target and when combined with its target gene MAP1LC3B, could be used as prognostic markers to guide identification of UM patients potentially responsive to this type of clinical intervention. We are currently working on elucidating the underlining cancer-killing mechanism of the EHMT2 inhibitor at genomic scale and exploring combinations of epigenetic drugs for improved therapeutic outcomes of primary and metastatic UM.