Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Citron, Francesca; Fabris, Linda

doi:10.3390/cancers12030682

Cited by 7 publications

(8 citation statements)

References 144 publications

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“…The landscape of the epigenome is emerging as a potential target for the therapy of cancers [ 26 , 27 , 28 , 29 ]. To date, there are numerous histone-modifying enzymes that can be categorized in writers, erasers, and readers.…”

Section: Discussionmentioning

confidence: 99%

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

Shang

Nguyen

Shu

et al. 2020

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

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

Shang

Nguyen

Shu

et al. 2020

Cancers

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“…Epigenetic gene silencing is increasingly being recognized as contributing to the development of cisplatin resistance. The treatment with demethylating agents, such as 5-aza-2′-deoxycytidine, resensitizes patients to platinum therapy, which is evidence of the critical importance of DNA methylation in drug resistance [ 250 , 251 ]. MAL transcript levels are higher in cis-platinum-resistant ovarian cell lines.…”

Section: Mal In Cancermentioning

confidence: 99%

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

Rubio-Ramos

Labat-de-Hoz

Correas

et al. 2021

Cells

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The MAL gene encodes a 17-kDa protein containing four putative transmembrane segments whose expression is restricted to human T cells, polarized epithelial cells and myelin-forming cells. The MAL protein has two unusual biochemical features. First, it has lipid-like properties that qualify it as a member of the group of proteolipid proteins. Second, it partitions selectively into detergent-insoluble membranes, which are known to be enriched in condensed cell membranes, consistent with MAL being distributed in highly ordered membranes in the cell. Since its original description more than thirty years ago, a large body of evidence has accumulated supporting a role of MAL in specialized membranes in all the cell types in which it is expressed. Here, we review the structure, expression and biochemical characteristics of MAL, and discuss the association of MAL with raft membranes and the function of MAL in polarized epithelial cells, T lymphocytes, and myelin-forming cells. The evidence that MAL is a putative receptor of the epsilon toxin of Clostridium perfringens, the expression of MAL in lymphomas, the hypermethylation of the MAL gene and subsequent loss of MAL expression in carcinomas are also presented. We propose a model of MAL as the organizer of specialized condensed membranes to make them functional, discuss the role of MAL as a tumor suppressor in carcinomas, consider its potential use as a cancer biomarker, and summarize the directions for future research.

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“…In fact, the majority of HDACi studies, including preclinical studies and clinical trials are mainly focused on Class I HDACs, since they are the main nuclear HDACs with high enzymatic activities and important physiological functions. However, in vivo HDACi toxicity observed up to date are also mainly caused by inhibiting HDAC1-3, the core nuclear histone deacetylase [116][117][118]. On the other hand, the concept that HDAC4 is a highly effective target is supported by the data presented here and it is not only more innovative, but also has the potential to significantly reduce toxicity.…”

Section: Discussionmentioning

confidence: 52%

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

Fan

Wang

et al. 2021

Cancers

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We have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC.

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Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

Cited by 7 publications

References 144 publications

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

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

The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer

A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer

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