Targeting the FBXO44/SUV39H1 Pathway in Cancer

靶向癌症中的 FBXO44/SUV39H1 通路

• 批准号: 10539330
• 负责人: CHARLES H. SPRUCK
• 金额: $ 43.71万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539330
• 关键词: Activated Natural Killer Cell; Binding; Cancer Patient; Cell Survival; Chromatin Remodeling Factor; Clinical; Coupled; DNA Damage; DNA Methylation; DNA biosynthesis; DNA replication fork; Data; Deacetylase; Development; Disease; Dose Limiting; Endogenous Retroviruses; Epigenetic Process; Exhibits; Gene Silencing; Genetic Transcription; Goals; Growth; Histone Deacetylase; Human; Human Genome; Immunotherapy; Infiltration; KDM1A gene; Ligands; Malignant Neoplasms; Mediating; Methyltransferase; Modification; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Normal Cell; NuRD complex; Nucleosomes; Organ; Pathway interactions; Pharmaceutical Preparations; Play; Poly(ADP-ribose) Polymerase Inhibitor; Prevention; Proteins; RNA interference screen; Regulatory Pathway; Relapse; Repetitive Sequence; Research; Resistance; Resolution; Retrotransposon; Role; Single Strand Break Repair; Somatic Cell; Stimulator of Interferon Genes; Surface; Therapeutic; Therapeutic Intervention; Toxic effect; Transcriptional Activation; Transcriptional Silencer Elements; Tumorigenicity; Viral; anti-PD1 therapy; antitumor effect; brca gene; cancer cell; cancer therapy; chemotherapy; chromatin modification; clinical application; cytotoxic; genome integrity; in silico; inhibitor; mimicry; mortality; mutant; new therapeutic target; pharmacologic; preclinical study; prevent; recruit; replication stress; response; side effect; synergism; treatment response; tumor; tumor growth; tumor progression; ubiquitin ligase

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.

项目摘要 重复元件（RE）占人类基因组的约45%，通常是转录沉默的， 尽管机制仍然难以捉摸。通过高含量的RNAi筛选，我们将FBXO 44鉴定为 癌细胞中RE的一种重要阻遏物。FBXO 44结合抑制性H3 K9 me 3修饰的核小体， 复制叉和募集的H3 K9 me 3甲基转移酶SUV 39 H1，泛素连接酶CRL 4 RBBP 4/7，和 组蛋白去乙酰化酶和染色质重塑复合物Mi-2/NuRD使DNA后RE转录沉默 复制的FBXO 44/SUV 39 H1抑制转录激活的卫星重复序列和内源性 逆转录病毒和逆转录转座子，导致DNA复制应激和刺激MAVS 和STING细胞内抗病毒途径，以促进降低的致瘤性和增强的免疫治疗 反应计算机模拟分析显示，FBXO 44表达与DNA复制应激呈负相关， 抗病毒途径，以及人类癌症中的细胞毒性T和自然杀伤（NK）细胞浸润。重要的是，我们发现 FBXO 44/SUV 39 H1在正常细胞中被认为是RE沉默，且它们的抑制不影响 RE或细胞活力时的H3 K9 me 3水平。我们的假设是FBXO 44/SUV 39 H1介导的RE元件 沉默是癌细胞的表观遗传脆弱性，其可能被靶向诱导病毒感染。 抑制肿瘤生长和进展并增强某些癌症疗效的模仿反应 治疗在这个建议中，我们将进行临床前研究，评估两个潜在的治疗应用 FBXO 44/SUV 39 H1通路靶向癌症：1）通过刺激FBXO 44/SUV 39 H1通路， 细胞内抗病毒途径和NK细胞识别;和2）通过以下途径增强PARP抑制剂功效： 此外，我们还将研究CRL 4 RBBP 4/7在REs中的作用。 泛素连接酶在FBXO 44/SUV 39 H1介导的RE沉默中的作用，并评估其用于癌症治疗的靶向。 这些研究可以揭示癌细胞的靶向表观遗传脆弱性，其抑制诱导病毒感染。 毫无疑问，模仿可以阻止肿瘤的生长和发展，提高癌症治疗的功效， 导致疾病死亡率的显著降低。