标题：STING is silenced by DNA methylation in primary brain tumors and is rescued by methyltransferase inhibition

作者：Justin Low, Vidya Chandramohan, Michelle Bowie, Michael Brown, Matthew Waitkus, Aaron Briley, Kevin Stevenson, Rebecca Fuller, Zachary Reitman, Andrea Muscat, Seethalakshmi Hariharan, Janell Hostettler, Nicholas Wong, Matthias Gromeier, David Ashley

网址:https://n.neurology.org/content/98/18_Supplement/1639

求助者：缘起缘灭

• 求助时间：2022/8/12 22:23:10
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• 文献摘要：

Objective: To determine how STING signaling is disrupted in gliomas, other primary brain tumors, and the normal brain. Background: The STING pathway is a critical sensor of cytosolic DNA and initiates inflammatory signaling in the context of viral infection and cancer. STING suppression has recently been described in a variety of solid tumors, but its role in brain tumors remains poorly understood. Here we investigate the mechanisms of STING signaling disruption in gliomas, and extend our analyses to the normal brain, other primary brain tumors, and extracranial tumors. Design/Methods: We used methylation arrays, RNA sequencing, and protein expression assays to probe STING pathway expression in patient-derived glioblastoma tissues and glioma cell culture systems. We additionally used published methylation array datasets to investigate the STING methylation landscape across cancer and non-cancerous neurologic disease states. Results: STING expression and function are suppressed in glioblastomas and other primary brain tumors. This suppression is mediated by promoter hypermethylation and is rare amongst extracranial cancers. However, neuroectoderm-derived cancers, and normal adult and fetal brain also exhibit methylation-mediated silencing, suggesting a neurodevelopmental origin for STING epigenetic silencing. In gliomas, we demonstrate that STING expression is suppressed specifically in malignant cells but is intact in immune and stromal cells in the tumor microenvironment. We further demonstrate that this epigenetic silencing is reversible via DNA methyltransferase (DNMT) inhibition in a manner that reconstitutes double-stranded DNA sensing and inflammatory signaling. Conclusions: STING silencing via promoter hypermethylation characterizes the normal and cancerous brain, correlates with an immunosuppressive microenvironment, and is therapeutically reversible by DNMT inhibitors. Disclosure: Dr. Low has nothing to disclose. Dr. Chandramohan has nothing to disclose. Mrs. Bowie has nothing to disclose. Dr. Brown has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Istari Oncology, Inc.. The institution of Dr. Brown has received research support from National Institute of Health . Dr. Brown has received intellectual property interests from a discovery or technology relating to health care. Matthew Waitkus has nothing to disclose. Mr. Stevenson has nothing to disclose. Miss Fuller has nothing to disclose. Dr. Reitman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Oakstone Publishing. Dr. Reitman has received intellectual property interests from a discovery or technology relating to health care. Ms. Muscat has nothing to disclose. Dr. Hariharan has nothing to disclose. Janell Hostettler has nothing to disclose. Dr. Wong has received stock or an ownership interest from Pacific Edge Limited. The institution of Dr. Wong has received research support from National Health and Medical Research Council. Prof. Gromeier has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ISTARI Oncology. Prof. Gromeier has received stock or an ownership interest from ISTARI Oncology. The institution of Prof. Gromeier has received research support from ISTARI Oncology. Prof. Gromeier has received intellectual property interests from a discovery or technology relating to health care. Prof. Gromeier has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with ISTARI Oncology. David Ashley has received personal compensation in the range of $0-$499 for serving as a Consultant for Jackson Laboratory. David Ashley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Diverse BioPharma. David Ashley has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Jackson Laboratory. David Ashley has received stock or an ownership interest from Diverse BioPharma. David Ashley has received intellectual property interests from a discovery or technology relating to health care. David Ashley has received intellectual property interests from a discovery or technology relating to health care. David Ashley has received intellectual property interests from a discovery or technology relating to health care.

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