Abstract
Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. Here, we determine that non-canonical histone signature acetylated H3 lysine 23 (H3K23ac)-binding protein tripartite motif-containing 24 (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. In multiple glioma cell lines and patient-derived glioma stem cells (GSCs), EGFR signaling promotes H3K23 acetylation and association with TRIM24. Consequently, TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Our findings uncover a pathway in which TRIM24 functions as a signal relay for oncogenic EGFR signaling and suggest TRIM24 as a potential therapeutic target for GBM that are associated with EGFR activation.
Highlights
Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood
To determine roles of histone modification in EGFR-driven gliomagenesis, we analyzed expression of histone H3 lysine 23 acetylation (H3K23ac), histone H3 lysine 27 trimethylation (H3K27me3), histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac)-four histone modifications associated with transcriptional regulation[8,19,20,21,22,23] using Western blotting in isogenic U87 and LN229 GBM cells with, or without, stable expression of the ligand-independent activated EGFR mutant, EGFRvIII. This analysis revealed that H3K23ac was significantly upregulated in EGFRvIII-expressing GBM cells compared with the controls, whereas expression of H3K27me[3], H3K4me[3], and H3K27ac were not affected (Fig. 1a)
Here, we reveal a novel mechanism of H3K23ac/tripartite motif-containing 24 (TRIM24)/ STAT3-mediated gliomagenesis driven by EGFR activation
Summary
Aberrant amplification and mutations of epidermal growth factor receptor (EGFR) are the most common oncogenic events in glioblastoma (GBM), but the mechanisms by which they promote aggressive pathogenesis are not well understood. We determine that non-canonical histone signature acetylated H3 lysine (H3K23ac)-binding protein tripartite motif-containing (TRIM24) is upregulated in clinical GBM specimens and required for EGFR-driven tumorigenesis. TRIM24 functions as a transcriptional co-activator and recruits STAT3, leading to stabilized STAT3-chromatin interactions and subsequent activation of STAT3 downstream signaling, thereby enhancing EGFR-driven tumorigenesis. Subsequent work identified acetylated proteins that are bound by acetyl lysine reader proteins containing binding bromodomain (BRD), demonstrating that PTM can exert its effect by recruiting chromatin binding proteins to regulate various cellular functions[5,6]. TRIpartite Motif-containing protein 24 (TRIM24), known as Transcription Intermediary Factor 1 alpha (TIF1α) is a reader of non-canonical histone signature H3K23ac[8]. TRIM24 was identified as a transcription cofactor of receptors such as estrogen receptor (ER) in breast cancer[8] and androgen receptor (AR) in prostate cancer[19] to interact with chromatin and these nuclear receptors via its tandem
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