Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors

Daskalakis, Michael; Brocks, David; Sheng, Yi; Islam, Saiful; Ressnerova, Alzbeta; Assenov, Yassen; Milde, Till; Oehme, Ina; Witt, Olaf; Goyal, Ashish; Kühn, Alexander; Hartmann, Mark; Weichenhan, Dieter; Jung, Manfred; Plass, Christoph

doi:10.1080/15384101.2018.1442623

Cited by 60 publications

(51 citation statements)

References 127 publications

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“…These epigenetic modifications may explain the polarization profiles such as tolerance or trained immunity, observed after various stimulations of innate cells (Saeed et al 2014). We hypothesized and confirmed in vivo that other elements than genes, especially HERVs which are known to be tightly controlled by epigenetic modifications (Daskalakis et al 2018), might be modulated in acute inflammatory situations. This has also been demonstrated in other pathophysiological contexts such as cancer (J.…”

Section: Discussionmentioning

confidence: 61%

Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn

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Jourdan

et al. 2018

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29 30 number of words: 5504 31 number of figures: 10 32 33 Keywords 34 Endogenous retroviruses -severe inflammatory injuries -septic shock -burn -trauma -transcriptome 35 -host response. 36 37 2 Abstract 38Although human endogenous retroviruses (HERVs) expression is a growing subject of interest, 39 no study focused before on specific endogenous retroviruses loci activation in severely injured 40 patients. Yet, HERV reactivation is observed in immunity compromised settings like some 41 cancers and auto-immune diseases. Our objective was to assess the transcriptional modulation of 42 HERVs in burn, trauma and septic shock patients. We analyzed HERV transcriptome with 43 microarray data from whole blood samples of a burn cohort (n=30), a trauma cohort (n=105) and 44 2 septic shock cohorts (n=28, n=51), and healthy volunteers (HV, n=60). We described 45 expression of the 337 probesets targeting HERV from U133 plus 2.0 microarray in each dataset 46 and then we compared HERVs transcriptional modulation of patients compared to healthy 47 volunteers. Although all 4 cohorts contained very severe patients, the majority of the 337 HERVs 48 was not expressed (around 74% in mean). Each cohort had differentially expressed probesets in 49 patients compared to HV (from 19 to 46). Strikingly, 5 HERVs were in common in all types of 50 severely injured patients, with 4 being up-modulated in patients. We highlighted co-expressed 51 profiles between HERV and nearby gene as well as autonomous HERV expression. We suggest 52 an inflammatory-specific HERV transcriptional response, and importantly, we introduce that the 53 HERVs close to immunity-related genes might have a role on its expression. 54 55 57 infected germinal cells and became integrated in our genome million years ago (Young, Stoye, 58 and Kassiotis 2013). These rare events happened several times in evolution. As retrotransposons, 59

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Section: Discussionmentioning

confidence: 61%

Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn

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Jourdan

et al. 2018

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“…HDACi can modify the acetylation status of histones, resulting in the induction of cell cycle arrest, apoptosis or differentiation ( Eckschlager et al, 2017 ). HDACi potentially re-activate HERVs, however, the beneficial or detrimental effects of epigenetic drugs on HERV modulation are currently discussed ( Chiappinelli et al, 2015 ; Hurst et al, 2016 ; Daskalakis et al, 2018 ; White et al, 2018 ).…”

Section: Herv-k and The Acquisition Of Cancer Hallmarks: Rationale Fomentioning

confidence: 99%

Human Endogenous Retrovirus K in the Crosstalk Between Cancer Cells Microenvironment and Plasticity: A New Perspective for Combination Therapy

et al. 2018

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Abnormal activation of human endogenous retroviruses (HERVs) has been associated with several diseases such as cancer, autoimmunity, and neurological disorders. In particular, in cancer HERV activity and expression have been specifically associated with tumor aggressiveness and patient outcomes. Cancer cell aggressiveness is intimately linked to the acquisition of peculiar plasticity and heterogeneity based on cell stemness features, as well as on the crosstalk between cancer cells and the microenvironment. The latter is a driving factor in the acquisition of aggressive phenotypes, associated with metastasis and resistance to conventional cancer therapies. Remarkably, in different cell types and stages of development, HERV expression is mainly regulated by epigenetic mechanisms and is subjected to a very precise temporal and spatial regulation according to the surrounding microenvironment. Focusing on our research experience with HERV-K involvement in the aggressiveness and plasticity of melanoma cells, this perspective aims to highlight the role of HERV-K in the crosstalk between cancer cells and the tumor microenvironment. The implications for a combination therapy targeted at HERVs with standard approaches are discussed.

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“…Thus, SETD1A could be a potential drug target for lung tumor treatment. At present, combination epigenetic therapy is widespread [34][35][36] , and our results provide a new candidate for combined treatment.…”

Section: Discussionmentioning

confidence: 64%

Histone methyltransferase SETD1A participates in lung cancer progression

Wang

Gong

et al. 2020

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Lung cancer is the leading cause of cancer-related death worldwide, with an estimated 1.2 million deaths each year. Despite advances in lung cancer treatment, 5-year survival rates are lower than ~ 15%, which is attributed to diagnosis limitations and current clinical drug resistance. Recently, more evidence has suggested that epigenome dysregulation is associated with the initiation and progress of cancer, and targeting epigenome-related molecules improves cancer symptoms. Interestingly, some groups reported that the level of methylation of histone 3 lysine 4 (H3K4me3) was increased in lung tumors and participated in abnormal transcriptional regulation. However, a mechanistic analysis is not available. In this report, we found that the SET domain containing 1A (SETD1A), the enzyme for H3K4me3, was elevated in lung cancer tissue compared to normal lung tissue. Knockdown of SETD1A in A549 and H1299 cells led to defects in cell proliferation and epithelial-mesenchymal transition (EMT), as evidenced by inhibited WNT and TGFβ pathways, compared with the control group. Xenograft assays also revealed a decreased tumor growth and EMT in the SETD1A silenced group compared with the control group. Mechanistic analysis suggested that SETD1A might regulate tumor progression via several critical oncogenes, which exhibited enhanced H3K4me3 levels around transcriptional start sites in lung cancer. This study illustrates the important role of SETD1A in lung cancer and provides a potential drug target for treatment.

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Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors

Cited by 60 publications

References 127 publications

Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn

Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn

Human Endogenous Retrovirus K in the Crosstalk Between Cancer Cells Microenvironment and Plasticity: A New Perspective for Combination Therapy

Histone methyltransferase SETD1A participates in lung cancer progression

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