REST upregulates gremlin to modulate diffuse intrinsic pontine glioma vasculature

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models. DIPGs are vascularized tumors and interestingly, REST loss in DIPG cells also caused a substantial decline in tumor vasculature as measured by a decrease in CD31 and VEGFR2 staining. These observations were validated in vitro, where a significant decline in tube formation by human umbilical vein endothelial cells (HUVEC) was seen following REST-loss in DIPG cells. Mechanistically, REST controlled the secretion of a pro-angiogenic molecule and ligand for VEGFR2 called Gremlin-1 (GREM-1), and was associated with enhanced AKT activation. Importantly, the decline in tube formation caused by REST loss could be rescued by addition of recombinant GREM-1, which also caused AKT activation in HUVECs and human brain microvascular endothelial cells (HBMECs). In summary, our study is the first to demonstrate autocrine and paracrine functions for REST in DIPG development. It also provides the foundation for future investigations on anti-angiogenic therapies targeting GREM-1 in combination with drugs that target REST-associated chromatin remodeling activities.

Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG

“…In contrast, regions exhibiting reduced H3K27ac and H3K27me3 due to Our further analyses reveal that Corin treatment results in increased H3K4me1 and H3K27ac at genomic regions enriched in binding sites for transcription factors, such as REST, which plays an important role in silencing neuronal genes in non-neuronal cells (Chong et al, 1995;Laurent et al, 2015;Lee et al, 2005;Schoenherr et al, 1996;Sun et al, 2010). Consistently, recent work shows that REST is overexpressed in a subset of DIPGs, and that the loss of REST suppresses the growth of DIPG xenografts (Shaik et al, 2018). We hypothesize that dual targeting of both histone acetylation and methylation with Corin allows for more comprehensive and sustained inhibition of transcriptional silencing complexes associated with REST and other transcription factors than either HDAC or LSD1 inhibitors alone.…”

Transcriptome signatures associated with meningioma progression

“…GREM2, also known as PRDC (Protein Related to Dan and Cerberus) encodes for a member of the DAN family of secreted proteins which constitute a subgroup of inhibitors of the BMP pathway [36]; GREM2 appears to be more efficient in inhibiting BMP2 and BMP4 than TGFβ [50]. Its function during development is not well understood, although it has been associated with osteogenesis and cardiac development [35, 54]; GREM1 has been associated with increased vascular proliferation and carcinogenesis in diffuse intrinsic pediatric glioma and other gliomas [8, 20, 47]. GREM2 function in cancer biology and in meningioma is not known.…”

Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion

“…Recent studies indicated that REST modulates the vasculature in diffuse intrinsic pontine glioma (DIPG). REST has been shown to up-regulate the pro-angiogenic molecule gremlin-1 [25]. Inhibition of REST in DIPG caused a substantial decline in tumor vasculature, as measured by decreased CD31 and VEGFR2 staining, and reduced tube formation.…”