Abstract
Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.
Highlights
Statistical analyses suggest that Gastrointestinal stromal tumors (GISTs) are one of the most common types of mesenchymal tumors, and GISTs originate from ICCs, further affecting the gastrointestinal tract [1, 2]
BRD9 is expressed at high levels in GIST tissues To investigate the functional role of BRD9 in GISTs, we validated the expression of BRD9 in clinically confirmed GIST specimens, which included 38 GIST tissues that were compared with 25 adjacent nontumor tissues
We investigated the role of BRD9 in GISTs
Summary
Statistical analyses suggest that GISTs (gastrointestinal stromal tumors) are one of the most common types of mesenchymal tumors, and GISTs originate from ICCs (interstitial cells of Cajal), further affecting the gastrointestinal tract [1, 2]. Mutations of KIT (tyrosine kinase) are responsible for 75–80% of GISTs, whereas 5–10% of confirmed cases occur due to activating mutations of PGDFRA (platelet-derived growth factor receptor alpha) [3, 4]. These mutations further affect downstream signaling pathways to promote tumorigenic cellular proliferation. Clinical analysis has confirmed that more than 50% of patients develop imatinib resistance within 2 years of treatment [8, 9] These patients develop secondary KIT and PDGFRA mutations via activation of alternative oncogenic signaling pathways [10]. It is very important to understand the molecular mechanism underlying GIST malignancy to develop novel therapeutic options
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