# Targeting the FBXO44/SUV39H1 Pathway in Cancer

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2022 · $441,716

## Abstract

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.

## Key facts

- **NIH application ID:** 10343545
- **Project number:** 1R01CA267103-01
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** CHARLES H. SPRUCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,716
- **Award type:** 1
- **Project period:** 2021-12-10 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10343545

## Citation

> US National Institutes of Health, RePORTER application 10343545, Targeting the FBXO44/SUV39H1 Pathway in Cancer (1R01CA267103-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10343545. Licensed CC0.

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