Monday, June 5, 2023
6/5/2023
PROJECT SUMMARY Repetitive elements (REs) compose ~45% of the human genome and are normally transcriptionally silenced in somatic cells, although the mechanism had remained elusive. Through a high-content RNAi screen, we identified the largely uncharacterized protein FBXO44 as an essential repressor of REs in breast cancer cells. FBXO44 bound repressive histone H3 lysine 9 trimethylated (H3K9me3) nucleosomes at the replication fork and recruited H3K9me3 methyltransferase SUV39H1, ubiquitin ligase CRL4RBBP4/7, and histone deacetylase and chromatin- remodeling complex Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition transcriptionally reactivated endogenous retroviruses (ERVs) and retrotransposons (e.g. Alu, LINE-1) in breast cancer cells, leading to extensive DNA replication stress and stimulation of RIG-I/MDA5-MAVS and cGAS-STING intracellular antiviral pathways to promote enhanced immunogenicity and decreased tumorigenicity. In silico analysis revealed the FBXO44/SUV39H1 pathway inversely correlated with DNA replication stress, antiviral pathways, and cytotoxic T and natural killer (NK) cell infiltration in human breast tumors. Importantly, FBXO44/SUV39H1 were found dispensable for RE silencing in normal cells and their inhibition had no effect on H3K9me3 levels, DNA replication stress, or viability, suggesting a therapeutic window. Our hypothesis is that FBXO44/SUV39H1-mediated RE silencing is an epigenetic vulnerability of breast cancer cells that could be targeted to inhibit tumor growth/progression and enhance the efficacy of certain antitumor therapies through the unique mechanism of induced viral mimicry. In this proposal, we will evaluate 3 potential therapeutic applications of FBXO44/SUV39H1 pathway targeting in the treatment of estrogen receptor (ER)+ breast cancers based on our preliminary data: 1) prevention of bone metastasis relapse through stimulation of NK cell recognition and killing of dormant breast cancer cells; 2) enhancement of immune checkpoint blockade (ICB) therapy through stimulation of IFN signaling and intratumoral infiltration of cytotoxic T cells; and 3) synergy with PARP inhibitors through induction of DNA replication stress and double-strand breaks (DSBs) at REs. These studies could lead to the development of a safe and effective therapeutic approach that selectively induces viral mimicry in ER+ breast cancer cells to prevent bone metastasis relapse and enhance the efficacy of ICB and PARP inhibitor therapies, undoubtedly leading to a significant reduction in disease mortality.
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