Osteosarcoma (OS) is the most common paediatric primary bone tumour; the survival is related to the response to chemotherapy and development of metastases. Moreover, it is a highly metastatic tumour, and pulmonary metastases are the most common cause of death. Recent evidences showed that in osteosarcoma primary tumours are genetically homogeneous but epigenetically heterogeneous and this heterogeneity increased in metastatic disease. In a previous whole exome study, we observed an involvement of KMT2C in the carcinogenesis of OS. This gene has never been studied in OS and we found that it was expressed in OS samples. Particularly, we performed the immunohistochemical and gene expression analysis of KMT2C in 32 samples of patients with diagnosis of OS with known clinic-pathological data and we analysed the expression of genes involved in the metastatic pathway in four OS cell lines by blocking the KMT2C expression using siRNA. We found a nuclear-cytoplamic trafficking of KMT2C and the cytoplasmic localization was higher than the nuclear localization (p
Although the advances in understanding of the aetiology and biology of OS, the recent clinical trials of OS have shown only modest progress. Clinical outcomes for patients have not improved over the past 30 years and there are currently no approved target antimetastatic therapies for OS in wide clinical use. More than 75% of OS metastases occur in the lung and these are the cause of most of OS-related deaths.
Metastasis is a complex multistep process that is not fully understood. It has been shown that altered transcriptional programs play a role in metastatic tumor progression and they have been associated with metastatic colonization of specific secondary organs. Recently, epigenetic changes have been associated with transcriptional changes during metastasis and it was been demonstrated that chromatin changes drive the metastatic phenotype across various cancers.
Our previous studies led us to identify KMT2C as gene that may be involve in OS metastatic progression. Indeed, given the potential roles of mutations in enhancer regulators such as KMT2C in cancer pathogenesis, increasing our understanding of how enhancer-mediated process function in cellular growth should lead to future research efforts. From our data, we obtained valuable information about KMT2C in OS: we found a nuclear-cytoplasmic trafficking that could have a role in OS progression probably linked to the consequent change of its function and we found that it affected the enhancer activity of genes involved in OS progression playing the role of both oncogene and oncosuppressor, particularly in the degradation and attachment of tumor cells to ECM. However, a better understanding of the role of KMT2C in OS carcinogenesis and progression is necessary because epigenetic therapy is promising for cancer treatment in the light of recent developments in this field. Moreover, chromatin modifiers are already recognized as a cancer therapy target and clinical trials for the treatment of MLL1/KMT2A-fusion leukemia provide evidence for the development of drugs targeting the members of KMT2 family.
Therefore, this study could offer the opportunity to identify a potential therapeutic target to obtain personalized therapy and increase the survival rate of young patients affected by OS.