Scientific activity covers the area of molecular oncology, epigenetics and epigenomics, and non-coding RNAs. Over the years, we have studied the role of the transcription and self-renewal factor OCT4 in the etiopathogenesis of ovarian cancer by marking its importance in defining survivalrates, metastasis formation, chemoresistance and escape from immune surveillance.
- miRNAs and stemness in cancer cells and embryonic stem cells
We have shown that miR-335 coordinates embryonic stem cell self-renewal potential and cell cycle control using the transcription factor OCT4 and the Retinoblasm protein pRB as targets (Schoeftner et al., Stem Cells 2013).
By studying the role of the transcription and self-renewal factor OCT4, we also showed that OCT4 drives ovarian tumor aggressiveness by involving a circuit including not only microRNA and pRb, but also PP1, Aurora B and components of the chromosal passenger complex (CPC) to primarily target the mitotic stability of the tumor cell (Comisso et al., Oncogene 2017). Activation of this pathway in ovarian cancer patients leads to extremely poor survival, identifying OCT4-controlled genomic stability pathways as an attractive target for the treatment of ovarian cancer patients with pronounced stemness characteristics.
- Control of gene expression by pseudogene lncRNAs
More recently, we have shown that lncRNA -pseudogenes of OCT4 play a crucial role in controlling parental gene expression both during development and in the tumor context. That is, we found that lncRNA expression of an OCT4 pseudogene suppresses parental gene expression by depositing an epigenetic silencer complex on its promoter in a conserved manner in mouse embryonic stem cells and human ovarian cancer cells. This reveals a novel mechanistic pathway in which pseudogen-derived lncRNAs acquire a new biological function to regulate parental gene expression in trans mode (Scarola et al., Nat. Comm 2015; Scarola et al., Commun Biology 2020; Schoeftner et al., Methods Mole Biol., 2021).
In the recent period, then, an important strand of research turns the spotlight on the control of gene expression mediated by silencing complexes supervised by the OCT4 pseudogene lncRNA: the molecular mechanisms by which this lncRNA can modulate both the expression of the ancestral protein in trans and that of other targets in the genome and thus the related phenomena of drug resistance and immune-escape mESCs are being dissected.
- ncRNA and telomere function
In collaboration with the University of Trieste, we are also studying the role of ncRNAs in controlling telomere function. MiRNAs that control telomeres have been studied by targeting their regulatory proteins (Dinami et al. 2014; Dinami et al. 2017). Next, pathways have been identified that suppress the formation of RNA:DNA hybrids at telomeres (Petti et al. 2019), and 2,2,7-trimethyl guanosine RNA capping of human telomerase has been shown to direct telomere maintenance in lung cancer cells (Buemi et al. 2021).