Clinical advances in targeting epigenetics for cancer therapy

Feng, Shengrui; Carvalho, Daniel D. De

doi:10.1111/febs.15750

Cited by 66 publications

(63 citation statements)

References 189 publications

(235 reference statements)

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“…Indeed, a recent study showed an imbalance in ADAR1 and ADAR2 enzyme expression in HB tumors, accompanied by global RNA hypoediting. However, the authors also reported specific hyperediting of the BLCAP transcript, which is a highly conserved gene with tumor suppressor activities [18,217] . Despite the fact that this field requires deeper understanding, the study of this new epigenetic mechanism could contribute to the understanding of HB development and the design of novel "epidrugs" for the treatment of this and other tumors.…”

Section: Rna Editingmentioning

confidence: 98%

Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of noncoding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.

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Section: Rna Editingmentioning

confidence: 98%

Epigenetics in hepatoblastoma

Clavería-Cabello¹,

Arechederra²,

Berasain³

et al. 2021

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“…Both these modifications serve as molecular markers for “reader” proteins which subsequently recruit chromatin remodelers and non‐coding RNA to transduce downstream signaling mechanisms. These chemical modifications can also be reversed by “erasers” [106] . Dysregulation of these epigenetic processes is now recognized as a universal feature of cancers, with genome‐wide alterations in epigenetic profiles frequently detected in adult and pediatric cancers, as is the genetic mutation of “writer”, “readers” and “erasers”.…”

Section: Epigeneticsmentioning

confidence: 99%

“…Dysregulation of these epigenetic processes is now recognized as a universal feature of cancers, with genome‐wide alterations in epigenetic profiles frequently detected in adult and pediatric cancers, as is the genetic mutation of “writer”, “readers” and “erasers”. However, due to the reversible nature of epigenetic modification, targeted agents against these processes are being widely investigated [106] …”

Section: Epigeneticsmentioning

confidence: 99%

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

et al. 2021

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Copper is an essential transition metal frequently increased in cancer known to strongly influence essential cellular processes. Targeted therapy protocols utilizing both novel and repurposed drug agents initially demonstrate strong efficacy, before failing in advanced cancers as drug resistance develops and relapse occurs. Overcoming this limitation involves the development of strategies and protocols aimed at a wider targeting of the underlying molecular changes. Receptor Tyrosine Kinase signaling pathways, epigenetic mechanisms and cell metabolism are among the most common therapeutic targets, with molecular investigations increasingly demonstrating the strong influence each mechanism exerts on the others. Interestingly, all these mechanisms can be influenced by intracellular copper. We propose that copper chelating agents, already in clinical trial for multiple cancers, may simultaneously target these mechanisms across a wide variety of cancers, serving as an excellent candidate for targeted combination therapy. This review summarizes the known links between these mechanisms, copper, and copper chelation therapy.

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“…Inhibiting DNA methyltransferases (DNMTs) may avoid hypermethylation of CDH1 and tumor suppressors, while the inhibitory chromatin-modifying effects of EZH2 may represses PRC2 activity. The blocking of histone deacetylases (HDACs) may prevent histone modifications implicated in cancer [ 101 , 102 ]. Targeting epigenetic- and chromatin-related EMT processes in combination with standard therapeutic approaches such as ADT should be a promising strategy for improving disease outcome in PCa.…”

Section: Clinical Trialsmentioning

confidence: 99%

Epithelial–Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics

Chaves

Melo

Saggioro

et al. 2021

Genes

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Prostate cancers may reactivate a latent embryonic program called the epithelial–mesenchymal transition (EMT) during the development of metastatic disease. Through EMT, tumors can develop a mesenchymal phenotype similar to cancer stem cell traits that contributes to metastasis and variation in therapeutic responses. Some of the recurrent somatic mutations of prostate cancer affect EMT driver genes and effector transcription factors that induce the chromatin- and androgen-dependent epigenetic alterations that characterize castrate-resistant prostate cancer (CRPC). EMT regulators in prostate cancer comprise transcription factors (SNAI1/2, ZEB1, TWIST1, and ETS), tumor suppressor genes (RB1, PTEN, and TP53), and post-transcriptional regulators (miRNAs) that under the selective pressures of antiandrogen therapy can develop an androgen-independent metastatic phenotype. In prostate cancer mouse models of EMT, Slug expression, as well as WNT/β-Catenin and notch signaling pathways, have been shown to increase stemness potential. Recent single-cell transcriptomic studies also suggest that the stemness phenotype of advanced prostate cancer may be related to EMT. Other evidence correlates EMT and stemness with immune evasion, for example, activation of the polycomb repressor complex I, promoting EMT and stemness and cytokine secretion through RB1, TP53, and PRC1. These findings are helping clinical trials in CRPC that seek to understand how drugs and biomarkers related to the acquisition of EMT can improve drug response.

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Clinical advances in targeting epigenetics for cancer therapy

Cited by 66 publications

References 189 publications

Epigenetics in hepatoblastoma

Epigenetics in hepatoblastoma

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

Epithelial–Mesenchymal Transition Signaling and Prostate Cancer Stem Cells: Emerging Biomarkers and Opportunities for Precision Therapeutics

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