{"title":"靶向FBXO44/SUV39H1引发肿瘤细胞特异性DNA复制应激和病毒模仿。","authors":"Jia Z Shen, Charles Spruck","doi":"10.15698/cst2021.03.245","DOIUrl":null,"url":null,"abstract":"<p><p>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 immunotherapy drugs. In our study (Shen <i>et al.</i> (2020), Cell, doi: 10.1016/j.cell.2020.11.042), through a high-content RNAi screen we identified FBXO44 as a key regulator of H3K9me3-mediated transcriptional silencing of REs in cancer cells. Inhibition of FBXO44 or its co-factor SUV39H1 stimulated antiviral pathways and interferon (IFN) signaling and induced replication stress and DNA double-strand breaks (DSBs) in cancer cells, leading to restricted tumor growth and synergy with anti-PD-1 therapy (Figure 1). Figure 1FIGURE 1: Graphical representation of this study.FBXO44/SUV39H1 targeting activates REs that elicit DNA replication stress and viral mimicry in cancer cells, leading to tumor growth arrest and enhanced immunotherapy response.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2021-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921849/pdf/","citationCount":"1","resultStr":"{\"title\":\"Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry.\",\"authors\":\"Jia Z Shen, Charles Spruck\",\"doi\":\"10.15698/cst2021.03.245\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 immunotherapy drugs. In our study (Shen <i>et al.</i> (2020), Cell, doi: 10.1016/j.cell.2020.11.042), through a high-content RNAi screen we identified FBXO44 as a key regulator of H3K9me3-mediated transcriptional silencing of REs in cancer cells. Inhibition of FBXO44 or its co-factor SUV39H1 stimulated antiviral pathways and interferon (IFN) signaling and induced replication stress and DNA double-strand breaks (DSBs) in cancer cells, leading to restricted tumor growth and synergy with anti-PD-1 therapy (Figure 1). Figure 1FIGURE 1: Graphical representation of this study.FBXO44/SUV39H1 targeting activates REs that elicit DNA replication stress and viral mimicry in cancer cells, leading to tumor growth arrest and enhanced immunotherapy response.</p>\",\"PeriodicalId\":36371,\"journal\":{\"name\":\"Cell Stress\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2021-02-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921849/pdf/\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Stress\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.15698/cst2021.03.245\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Stress","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.15698/cst2021.03.245","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 1
摘要
重复元件(REs)通常通过抑制表观遗传修饰在体细胞中转录沉默,这些修饰被认为包括DNA甲基化和组蛋白修饰,如去乙酰化、H3K9me3和H4K20me3。然而,目前尚不清楚在快速生长的癌细胞中,RE沉默是如何通过DNA复制周期维持的。另一方面,癌细胞中超过耐受阈值水平的内源性逆转录因子的再激活,如用DNA去甲基化剂或HDAC或LSD1抑制剂治疗,可以诱导病毒模仿反应,从而增强某些癌症治疗,包括免疫治疗。然而,这些药物也会影响正常细胞,并呈现明显的副作用。因此,揭示癌细胞特异性RE沉默机制可以为开发新一代癌症免疫治疗药物提供基础。在我们的研究中(Shen et al. (2020), Cell, doi: 10.1016/j.c ells. 2020.11.042),通过高含量RNAi筛选,我们发现FBXO44是h3k9me3介导的肿瘤细胞REs转录沉默的关键调节因子。抑制FBXO44或其辅助因子SUV39H1刺激了癌细胞中的抗病毒途径和干扰素(IFN)信号传导,诱导复制应激和DNA双链断裂(DSBs),从而限制了肿瘤生长和与抗pd -1治疗的协同作用(图1)。FBXO44/SUV39H1靶向激活肿瘤细胞中引起DNA复制应激和病毒模仿的REs,导致肿瘤生长停滞和增强免疫治疗反应。
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 immunotherapy drugs. In our study (Shen et al. (2020), Cell, doi: 10.1016/j.cell.2020.11.042), through a high-content RNAi screen we identified FBXO44 as a key regulator of H3K9me3-mediated transcriptional silencing of REs in cancer cells. Inhibition of FBXO44 or its co-factor SUV39H1 stimulated antiviral pathways and interferon (IFN) signaling and induced replication stress and DNA double-strand breaks (DSBs) in cancer cells, leading to restricted tumor growth and synergy with anti-PD-1 therapy (Figure 1). Figure 1FIGURE 1: Graphical representation of this study.FBXO44/SUV39H1 targeting activates REs that elicit DNA replication stress and viral mimicry in cancer cells, leading to tumor growth arrest and enhanced immunotherapy response.
Cell StressBiochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍:
Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging.
The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.