Epigenetic Targeting of Mcl-1 Is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

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.

Epigenetic targeting of SLC30A3 by HDAC1 is related to the malignant phenotype of glioblastoma

“…Then, the mechanistical assay validated that the SE‐mediated H3K27ac modification is responsible for the downregulation of SLC30A3 in GBM. The similar mechanism of action has also been reported in a recent report where GBM harbors a SE around the Mcl‐1 locus, and THZ1, a SE blocker, elicited an impairment of the Mcl‐1 enhancer region, resulting in an inhibition of Mcl‐1 transcript and protein levels 22 …”

Neferine induces p38 MAPK/JNK1/2 activation to modulate melanoma proliferation, apoptosis, and oxidative stress

“…Apoptosis is a self-destructive process of cell stress, resulting in cell death and reduced cell viability, especially in tumor cells. Some biomarkers are used to monitor the process of apoptosis, including caspases (23), mitochondrial potential (24), and sub G1 group (25). Studies have shown that the main internal and external causes of apoptosis are related to caspases, including caspase-3 and/or caspase-9 (26).…”

Critical View of Novel Treatment Strategies for Glioblastoma: Failure and Success of Resistance Mechanisms by Glioblastoma Cells

“…Additionally, the anti-apoptotic Bcl-2 family member myeloid cell leukemia factor-1 (Mcl-1), which interferes in early cascade events by suppressing cytochrome c release from mitochondria, is highly expressed in human glioblastoma (Michels et al, 2005;Karpel-Massler et al, 2017). High levels of Mcl-1 mediate BH3-mimetic resistance, suggesting that a dual inactivation of Bcl-2/Bcl-xL and Mcl-1 is necessary for apoptosis of glioblastoma cells (Kouri et al, 2012;Karpel-Massler et al, 2017;Shang et al, 2020). AT-101, a small molecule targeting Mcl-1, is presently being examined in a clinical trial (Xiang et al, 2018).…”

“…Although inhibition of Mcl-1 has received certain attention as a potential drug target, only slowly implemented in clinical applications and poses challenges in glioblastoma treatment due to high molecular weight and the blood brain barrier. With the aim to overcome such drawbacks the use of combinatory approaches is further explored (Tron et al, 2018;Shang et al, 2020).…”