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- Title
Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas.
- Authors
Sweha, Stefan R.; Chung, Chan; Natarajan, Siva Kumar; Panwalkar, Pooja; Pun, Matthew; Ghali, Amer; Bayliss, Jill; Pratt, Drew; Shankar, Anand; Ravikumar, Visweswaran; Rao, Arvind; Cieslik, Marcin; Wilder-Romans, Kari; Scott, Andrew J.; Wahl, Daniel R.; Jessa, Selin; Kleinman, Claudia L.; Jabado, Nada; Mackay, Alan; Jones, Chris
- Abstract
keyimage.jpg STAT3 inhibition for H3.3G34R/V gliomas: High-grade gliomas with arginine or valine substitutions at the glycine-34 residue on histone H3.3 (H3.3G34R/V gliomas) carry a poor prognosis. Here, Sweha and colleagues investigated the epigenetics of these tumors, finding activating epigenetic modifications on histone H3 lysine residues, as well as DNA promoter hypomethylation. They also found redistribution of repressive histone marks at the leukemia inhibitory factor (LIF) locus, leading to increased LIF abundance and secretion. LIF activated STAT3 signaling, which the authors targeted with a blood-brain barrier–permeable small-molecule inhibitor called WP1066. When given to mice carrying H3.3G34R/V tumors, WP1066 suppressed tumor growth, suggesting that inhibition of STAT3 signaling may be of therapeutic value in H3.3G34R/V gliomas. High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier–penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors.
- Subjects
HISTONES; GLIOMAS; LEUKEMIA inhibitory factor; BRAIN tumors; LABORATORY mice; STAT proteins; EPIGENETICS
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 615, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abf7860