Deciphering adaptive mechanisms of ovarian cancer to mitochondrial complex I ablation as an anticancer strategy: the role of Differentiated Embryonic Chondrocyte expressed gene 1 (DEC1)

High Grade Serous Ovarian Cancer (HGSOC) is the most lethal gynecological neoplasm and the fifth most common cancer-related cause of death in women worldwide. Converting carcinomas into benign oncocytomas has been suggested as a promising anti-cancer strategy, and observations on oncocytic tumors have highlighted the involvement of mitochondrial respiratory chain Complex I mutations in the low proliferative capacities of such benign cancer cells. Complex I was hence proposed and then proved to be an attractive molecular target for various solid tumors treatment, including HGSOC. However, following an initial phase characterized by growth slowdown, Complex I-dysfunctional tumors develop compensatory mechanisms that provide cancer cells with the ability to survive and resume their proliferation rate. Dissecting such adaptive mechanisms is crucial to devise a therapeutical approach that combines CI inhibition with the targeting of the molecular effectors responsible for the compensatory mechanisms that follow CI impairment. In HGSOC CI-deficient cells, PGC1α expression is increased, eliciting gene expression reprogramming that may contrast the energetic crisis within the cell through mitochondrial biogenesis and that may promote metastasis through neoangiogenesis trigger. DEC1 is a transcriptional factor whose overexpression in HGSOC tissues is associated to poor prognosis and that was described as PGC1α repressor. This thesis aims to assess DEC1 regulation in CI-ablated HGSOC models and to gauge DEC1-mediated effects that may impact on the adaptive mechanisms occurring after CI impairment. DEC1 is decreased in CI-deficient cells, due to the Integrated Stress Response activation and to proteasome turnover, which act synergistically. DEC1 drop was associated to prolonged survival in HGSOC CI-impaired cells upon glucose restriction. The downstream targets of DEC1 were investigated through RNA sequencing, revealing a prominent effect on the transcription of genes related to the cytokines signaling and the inflammatory response, which are known to positively contribute to HGSOC progression and CI-deficiency adaptation.