Targeting the FBXO44/SUV39H1 Pathway in Cancer

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PROJECT SUMMARY Repetitive elements (REs) compose ~45% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through a high-content RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound repressive H3K9me3-modified 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 activated satellite repeats and endogenous retroviruses and retrotransposons in cancer cells, leading to DNA replication stress and stimulation of MAVS and STING intracellular antiviral pathways to promote decreased tumorigenicity and enhanced immunotherapy response. In silico analysis revealed that FBXO44 expression inversely correlated with DNA replication stress, antiviral pathways, and cytotoxic T and natural killer (NK) cell infiltration in human cancers. Importantly, we found that FBXO44/SUV39H1 are dispensable for RE silencing in normal cells and their inhibition did not affect H3K9me3 levels at REs or cell viability. Our hypothesis is that FBXO44/SUV39H1-mediated RE element silencing is an epigenetic vulnerability of cancer cells that could potentially be targeted to induce viral mimicry responses that inhibit tumor growth and progression and enhance the efficacy of certain cancer therapies. In this proposal, we will perform preclinical studies that evaluate two potential therapeutic applications of FBXO44/SUV39H1 pathway targeting in cancer: 1) prevention of metastatic relapse through stimulation of intracellular antiviral pathways and NK cell recognition; and 2) enhancement of PARP inhibitor efficacy through induction of extensive DNA replication stress at REs. Moreover, we will investigate the role of the CRL4RBBP4/7 ubiquitin ligase in FBXO44/SUV39H1-mediated RE silencing and evaluate its targeting for cancer treatment. These studies could uncover a targetable epigenetic vulnerability of cancer cells whose inhibition induces viral mimicry to prevent tumor growth and progression and enhance the efficacy of cancer therapeutics, undoubtedly leading to a significant reduction in disease mortality.