The regulation of RNA Polymerase II mediated transcription by Caspase-8 in ovarian cancer.

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e18082 Background: According to the WHO, in 2018, the number of new cases and mortality worldwide due to ovarian cancer, were 295,414 and 184,799, respectively, making it one of the most lethal gynaecological cancers in the world. The standard therapy of ovarian cancers is still comprehensive cytoreductive surgery followed by a combination of platinum-taxane based primary chemotherapy. Second line therapies include Carboplatin or Cisplatin in combination with Paclitaxel, PLD or Gemcitabine, with or without Bevacizumab. Unfortunately, late stage ovarian cancer cases are still incurable, however, several new drugs are under development or are undergoing clinical trials. At present, these new approaches can only stabilize the disease or delay its recurrence. Caspase-8, the predominant initiator of the extrinsic apoptotic pathway, also plays critical roles in a number of other non-apoptotic functions. It is also frequently down-regulated in ovarian cancer and we wanted to understand how this down-regulation could support the development of ovarian cancer. Methods: The analysis of the association between CASP8 expression and patient prognosis in ovarian cancer patients found that low CASP8 expression was significantly correlated with poor OS, with a median OS of 37.43 (low expression) and 49.97 (high expression) months, and higher clinical stages. CRISPR/Cas9 mediated CASP8 KO in multiple high- and low-grade ovarian cancer cell lines resulted in significant increases in their invasiveness. Results: Caspase-8 interactome analysis revealed that it can regulate the RNA Pol II mediated transcription, which was corroborated through multiple in vitro and ex vivo experiments. Global Transcriptomics and Proteomics analysis of the KO cells revealed significant upregulation of genes involved in metastasis, which was again verified in in vitro and ex vivo experiments. Additionally, the KO cells were significantly resistant towards standard chemotherapeutics like Carboplatin, a transcription inhibitor, either alone or in combination with Paclitaxel. Conclusions: Presently, we are working on orthotopic ovarian cancer mouse models to validate - the potential of Caspase-8 to regulate metastasis; and the targeting of RNA Pol II to sensitize them to standard chemotherapeutics. We are also developing organoid banks from patient derived ovarian cancer tissues, with low Caspase-8 expression, to validate the upregulation of genes identified in our ‘omics’ data and the potential of targeting them, along with RNA Pol II, to sensitize them to standard chemotherapeutics.