Orthogonal targeting of KDM6A/B and HDACs mediates potent therapeutic effects in <i>IDH1</i>-mutant glioma

Kayabölen, Alişan; Gn, Sahin; Seker-Polat, Fidan; Cingöz, Ahmet; Isik, Bekir; Acar, Simge; Wakimoto, Hiroaki; Dp, Cahill; Solaroğlu, İhsan; Cribbs, Adam P.; Oppermann, U.; Bagcı-Önder, Tugba

doi:10.1101/2020.11.26.400234

Cited by 3 publications

(6 citation statements)

References 76 publications

(136 reference statements)

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“…It was even reported that long-term treatment with mutant IDH inhibitors accelerated cell growth and shortened the in vivo survival [45]. Moreover, some studies suggested that mutant IDH inhibitors may interfere with therapeutic approaches targeting mutant IDHcaused vulnerabilities [36]. Therefore, even though mutant IDH enzymes create favorable conditions for tumorigenesis and selection of aggressive mutations, their inhibition may not always be effective in a tumor that has completed its stages of development.…”

Section: Mutant Idh Inhibitorsmentioning

confidence: 99%

“…Prolonged presence of mutant IDH1 renders most of these modifications irreversible, which may have critical importance for tumor progression. Based on this epigenetic reprogramming, we recently conducted chemical screening in IDH1-mutant GBM cells, including inhibitors of epigenetic enzymes [36]. We found that IDH1-mutant GBM cells are sensitive to different epigenetic enzyme inhibitors such as DNMT inhibitor 5-azacitidine, HMT inhibitor chaetocin, KDM inhibitor GSK-J4, and HDAC inhibitor belinostat.…”

Section: Combination Treatmentsmentioning

confidence: 99%

“…For example, it is known that IDH-mutant cells grow slower than the wildtype ones possibly because they have an altered metabolic profile due to the impaired TCA cycle [33], inhibition of mTOR and the ATP synthase [34], and changes in the expression of the LDHA enzyme [35]. There is an accumulating number of studies examining such specific vulnerabilities of IDH-mutant gliomas, including ours [36]. Therefore, exploiting the weaknesses of IDH-mutant gliomas and targeting them based on these deficiencies might be an equally, if not more, promising therapeutic strategy (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

2021

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Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.

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Section: Mutant Idh Inhibitorsmentioning

confidence: 99%

Section: Combination Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

2021

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“…Follow-up studies have been encouraging but mixed [25][26][27][28][29][30] . Interestingly three recent studies found that HDAC inhibitors may be speci cally effective in IDH1 mutant gliomas [31][32][33] . Histone deacetylases are ubiquitously expressed in various cell types and regulate multiple cellular processes.…”

Section: Introductionmentioning

confidence: 99%

HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma

Garrett

Albano

Carnwath

et al. 2022

Preprint

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Introduction: Low-grade and secondary high-grade gliomas frequently contain a mutation in the IDH1 metabolic enzyme that is hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Much of the previous research has focused on DNA methylation leaving histone modifications relatively under-studied. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials, however a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas and what are the down-stream gene targets. This information will allow clinicians to design more specific HDAC inhibitors as well as monitor for treatment response. Methods: A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of 110 epigenetic modifying drugs from 34 different epigenetic classes. The effect of LBH (Panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). Results: The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and Panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. Conclusions: The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study reports a previously under-described phenomenon of histone deacetylation induced by the IDH1 mutant enzyme and identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.

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“…Similarly, acetylation of histones leads to relaxed chromatin allowing aberrant gene expression whereas methylated histones are often associated with gene silencing [9,10]. Recent cancer genome sequencing studies revealed mutations in many epigenetic modifiers that are associated with various cancers [11], such as DNMT3A in acute myeloid leukemia [9,12], IDH1/2 in glioblastoma [13,14], CREBBP/EP300 in small-cell lung cancer [15] and ARID1A in gastric cancer [16]. These driver mutations are thought to act in part by increasing cellular plasticity during development of malignant tumors.…”

Section: Introductionmentioning

confidence: 99%

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Yedier-Bayram

Gokbayrak

Aksu

et al. 2021

Preprint

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Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To discover new drug targets for more targeted and personalized therapies, functional interrogation of epigenetic modifiers is essential. We therefore generated an epigenome-wide CRISPR-Cas9 knock-out library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution, depletion of essential genes and steady behaviors of non-targeting sgRNAs. From this, we discovered novel epigenetic modifiers besides previously known ones that regulate triple-negative breast cancer and prostate cancer cell fitness. With further validation assays, we confirmed the growth-regulatory function of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in triple negative breast cancer cells. Overall, we show that EPIKOL, a focused sgRNA library targeting approximately 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness and serve as a tool to offer novel anti-cancer targets. With its thoroughly generated epigenome-wide gene list, and the relatively high number of sgRNAs per gene, EPIKOL offers a great advantage to study functional roles of epigenetic modifiers in a wide variety of research applications, such as screens on primary cells, patient-derived xenografts as well as in vivo models.

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Orthogonal targeting of KDM6A/B and HDACs mediates potent therapeutic effects in IDH1-mutant glioma

Cited by 3 publications

References 76 publications

IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

IDH Mutations in Glioma: Double-Edged Sword in Clinical Applications?

HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma

EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

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