Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry
Repetitive elements (REs) are normally transcriptionally silenced in somatic cells by repressive epigenetic modifications, which are thought to include DNA methylation and histone modifications such as deacetylation, H3K9me3, and H4K20me3. Although, it is unclear how RE silencing is maintained through DNA replication cycles in rapidly growing cancer cells. On the other hand, the reactivation of endogenous retroelements beyond a threshold level of tolerance in cancer cells, such as by treatment with DNA demethylating agents or HDAC or LSD1 inhibitors, can induce viral mimicry responses that augment certain cancer therapies, including immunotherapy. However, these agents can also affect normal cells presenting obvious side effects. Therefore, uncovering cancer cell-specific RE silencing mechanisms could provide a basis for the development of a new generation of cancer (…)