Abstract
Apoptotic resistance remains a hallmark of glioblastoma (GBM), the most common primary brain tumor in adults, and a better understanding of this process may result in more efficient treatments. By utilizing chromatin immunoprecipitation with next-generation sequencing (CHIP-seq), we discovered that GBMs harbor a super enhancer around the Mcl-1 locus, a gene that has been known to confer cell death resistance in GBM. We utilized THZ1, a known super-enhancer blocker, and BH3-mimetics, including ABT263, WEHI-539, and ABT199. Combined treatment with BH3-mimetics and THZ1 led to synergistic growth reduction in GBM models. Reduction in cellular viability was accompanied by significant cell death induction with features of apoptosis, including disruption of mitochondrial membrane potential followed by activation of caspases. Mechanistically, THZ1 elicited a profound disruption of the Mcl-1 enhancer region, leading to a sustained suppression of Mcl-1 transcript and protein levels, respectively. Mechanism experiments suggest involvement of Mcl-1 in the cell death elicited by the combination treatment. Finally, the combination treatment of ABT263 and THZ1 resulted in enhanced growth reduction of tumors without induction of detectable toxicity in two patient-derived xenograft models of GBM in vivo. Taken together, these findings suggest that combined epigenetic targeting of Mcl-1 along with Bcl-2/Bcl-xL is potentially therapeutically feasible.
Highlights
The inherent resistance toward cell death is a challenge for glioblastoma therapy, the most common primary tumor for which no curative therapy currently exists [1,2,3]
Following chromatin immunoprecipitation with generation sequencing (CHIP-seq) with the H3K27ac antibody, we studied the presence of enhancers and super-enhancers in GBM tissues and GBM cell cultures, respectively
Through this analysis and in the context of a related pathway analysis (GREAT), we identified a super-enhancer around the Mcl-1 gene in glioblastoma, which was identified in several other GBM cultures (Figure 1a–e)
Summary
The inherent resistance toward cell death is a challenge for glioblastoma therapy, the most common primary tumor for which no curative therapy currently exists [1,2,3]. While apoptosis is regulated at several levels, the mitochondrial regulation is central and is governed by pro- and anti-apoptotic Bcl-2 family members [7,8,9]. The executer pro-apoptotic members are BAX and BAK, facilitating the liberation of cytochrome-c from the mitochondria following dissociation from their anti-apoptotic Bcl-2 family member interacting partners [9,10]. When Mcl-1 is inhibited, BAK is released and may facilitate cell death in concert with pro-apoptotic BAX [7,8,9,13]. With the advent of ABT-737 in 2005, it became feasible to interfere with both Bcl-2 and Bcl-xL and thereby induce cancer cell apoptosis [7,8,9,13]. Researchers sought to develop the concept even further and reached another milestone with the development of the state of the art BH3-mimetic, ABT-199 (Venetoclax), a specific inhibitor of Bcl-2 with drastically lower affinity to
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