Targeted demethylation of the SARI promotor impairs colon tumour growth

Wang, Qin; Dai, Lei; Wang, Yuan; Deng, Jie; Lin, Yi; Wang, Qingnan; Fang, Chao; Ma, Zongqing; Wang, Huiling; Shi, Gang; Cheng, Lin; Liu, Yi; Chen, Shuang; Li, Junshu; Dong, Zhexu; Su, Xiaolan; Yang, Lie; Zhang, Shuang; Jiang, Ming; Huang, Meijuan; Yang, Yang; Yu, Dechao; Zhou, Zong‐Guang; Wei, Yuquan; Deng, Hongxin

doi:10.1016/j.canlet.2019.01.040

Cited by 37 publications

(27 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies using CRISPR-based epigenome editing also reported the effects of targeted DNA demethylation using transient transfection. Wang et al reported that targeted DNA demethylation could last up to 23 days 23,24 , whereas Marx et al reported that increased gene expression by targeted DNA demethylation was maintained up to 80 days 23,24 . Furthermore, Josipović et al employed a different TET1-dCas9 construct from ours and induced targeted DNA demethylation.…”

Section: Discussionmentioning

confidence: 99%

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Hanzawa

Hashimoto

Yuan

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Recently, we reported ppARα-dependent DNA demethylation of the Fgf21 promoter in the postnatal mouse liver, where reduced DnA methylation is associated with enhanced gene expression after ppARα activation. However, there is no direct evidence for the effect of site-specific DNA methylation on gene expression. We employed the dCas9-SunTag and single-chain variable fragment (scFv)-TET1 catalytic domain (TET1CD) system to induce targeted DnA methylation of the Fgf21 promoter both in vitro and in vivo. We succeeded in targeted DnA demethylation of the Fgf 21 promoter both in Hepa1-6 cells and PPARα-deficient mice, with increased gene expression response to ppARα synthetic ligand administration and fasting, respectively. this study provides direct evidence that the DnA methylation status of a particular gene may determine the magnitude of the gene expression response to activation cues. In mammalian cells, DNA methylation is a major epigenetic modification, which regulates gene expression without alteration of the DNA sequence and thus plays a pivotal role in a myriad of physiological and pathological processes, including cell development and differentiation, genome imprinting, and tumorigenesis 1. We reported previously that the DNA methylation status of hepatic metabolic genes dynamically changes in early life, especially during the suckling period, thereby sequentially developing metabolic function in the liver to adapt to the drastic changes in the major nutrition source 2-4. Peroxisome proliferator-activated receptor-α (PPARα) is a nuclear receptor and a key regulator of hepatic lipid metabolism, which is activated by milk lipids as ligands at the onset of lactation. PPARα governs the transcription of major hepatic metabolism-related genes, and the activation of PPARα physiologically leads to DNA demethylation of fatty acid β-oxidation genes in the postnatal mouse liver 3,4. Of note, administration of a synthetic PPARα ligand to mouse dams during the perinatal period induced enhanced reduction of DNA methylation of PPARα target genes in the offspring liver, suggesting that the DNA methylation status of PPARα target genes can be modulated with ease during the perinatal period 3,4. A genome-wide analysis of DNA methylation revealed that a few PPARα target genes undergo ligand-activated, PPARα-dependent DNA demethylation during the perinatal period, and the DNA hypomethylation status of these persists into adulthood. Among these genes, which may be referred to as "epigenetic memory genes," we focused on fibroblast growth factor 21 (FGF21), which is a metabolic hormone derived from the liver and a master regulator of glucose and lipid metabolism 5-7 .

show abstract

Section: Discussionmentioning

confidence: 99%

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Hanzawa

Hashimoto

Yuan

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…We only observed the phenomenon of SARI deregulation during AOM/DSS-induced intestinal tumorigenesis, and further investigations are needed to elucidate the underlying mechanism and epigenetic regulation involved in this process, as indicated in colon cancer. 16 Various evidence has demonstrated the pro-oncogenic role of macrophages by the phenotype of promoting immunosuppressive tumour microenvironment formation. 9,10 The previous study by us indicated that more extensive macrophage infiltration into colon sections in SARI −/− mice compared with that in SARI WT mice in acute colitis.…”

Section: Discussionmentioning

confidence: 99%

“…The previous study by us demonstrated that SARI inhibiting tumour angiogenesis and colon tumour growth through directly targeting ceruloplasmin and inhibiting the HIF‐1α/VEGF axis . A recent study by us also determined the anti‐tumour role of SARI‐targeted demethylation system by inhibiting tumour proliferation, angiogenesis and promoting apoptosis in colon cancer . However, the role of SARI in tumour‐associated inflammation microenvironment is still elusive.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SARI suppresses colitis‐associated cancer development by maintaining MCP‐1‐mediated tumour‐associated macrophage recruitment

Dai

Liu

Yin

et al. 2019

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

SARI (suppressor of AP‐1, regulated by IFN) impaired tumour growth by promoting apoptosis and inhibiting cell proliferation and tumour angiogenesis in various cancers. However, the role of SARI in regulating tumour‐associated inflammation microenvironment is still elusive. In our study, the colitis‐dependent and ‐independent primary model were established in SARI deficiency mice and immuno‐reconstructive mice to investigate the functional role of SARI in regulating tumour‐associated inflammation microenvironment and primary colon cancer formation. The results have shown that SARI deficiency promotes colitis‐associated cancer (CAC) development only in the presence of colon inflammation. SARI inhibited tumour‐associated macrophages (TAM) infiltration in colon tissues, and SARI deficiency in bone marrow cells has no observed role in the promotion of intestinal tumorigenesis. Mechanism investigations indicated that SARI down‐regulates p‐STAT1 and STAT1 expression in colon cancer cells, following inhibition of MCP‐1/CCR2 axis activation during CAC development. Inverse correlations between SARI expression and macrophage infiltration, MCP‐1 expression and p‐STAT1 expression were also demonstrated in colon malignant tissues. Collectively, our results prove the inhibition role of SARI in colon cancer formation through regulating TAM infiltration.

show abstract

“…Various studies have demonstrated the anti‐tumour role of SARI in multiple cancers, including lung cancer, prostate cancer, B lymphoma and colon cancer . Previous studies by us indicated that SARI was down‐regulated in colon cancer and inhibits colon cancer growth through inhibiting the translational activity of HIF‐1α/VEGF and tumour angiogenesis . SARI is also involved in innate immunity and infection immunity .…”

Section: Introductionmentioning

confidence: 99%

SARI prevents ocular angiogenesis and inflammation in mice

Zhang

Dai

et al. 2020

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

SARI (Suppressor of AP-1, regulated by IFN-β) is known to play an important role in some systemic disease processes such an inflammatory conditions and cancer. We hypothesize that SARI may also play a role in ocular diseases involving inflammation and neovascularization. To explore our hypothesis, further, we investigated an endotoxin-induced uveitis (EIU) and experimental argon laser-induced choroidal neovascularization (CNV) model in SARI wild-type (SARI WT ) and SARI-deficient (SARI −/− ) mice. Through imaging, morphological and immunohistochemical (IHC) studies, we found that SARI deficiency exacerbated the growth of CNV. More VEGF-positive cells were presented in the retina of SARI −/− mice with CNV. Compared to SARI WT mice, more inflammatory cells infiltrated the ocular anterior segment and posterior segments in SARI −/− mice with EIU. Collectively, the results point to a potential dual functional role of SARI in inflammatory ocular diseases, suggesting that SARI could be a potential therapy target for ocular inflammation and neovascularization. K E Y W O R D Sage-related macular degeneration, choroidal neovascularization, regulated by IFN-β, Suppressor of AP-1, Uveitis, vascular endothelial growth factor

show abstract

Targeted demethylation of the SARI promotor impairs colon tumour growth

Cited by 37 publications

References 33 publications

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

SARI suppresses colitis‐associated cancer development by maintaining MCP‐1‐mediated tumour‐associated macrophage recruitment

SARI prevents ocular angiogenesis and inflammation in mice

Contact Info

Product

Resources

About