Dataset Information

Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer.

ABSTRACT: Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor suppressors and oncogenes, misregulating cellular differentiation and promoting cancer cell proliferation. Thus, targeting aberrant histone ubiquitination may be a viable strategy to reprogram transcription in cancer cells, in order to halt cellular proliferation and induce cell death, which is the basis for the ongoing development of therapies targeting histone ubiquitination. In this review, we present the normal functions of histone H2A and H2B ubiquitination and describe the role aberrant histone ubiquitination has in oncogenesis. We also describe the key benefits and challenges associated with current histone ubiquitination targeting strategies. As these strategies are predicted to have off-target effects, we discuss additional efforts aimed at developing synthetic lethal strategies and epigenome editing tools, which may prove pivotal in achieving effective and selective therapies targeting histone ubiquitination, and ultimately improving the lives and outcomes of those living with cancer.

SUBMITTER: Jeusset LM

PROVIDER: S-EPMC6406838 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer.

Jeusset Lucile M-P LM McManus Kirk J KJ

Cells 20190216 2

Histone ubiquitination is a critical epigenetic mechanism regulating DNA-driven processes such as gene transcription and DNA damage repair. Importantly, the cellular machinery regulating histone ubiquitination is frequently altered in cancers. Moreover, aberrant histone ubiquitination can drive oncogenesis by altering the expression of tumor suppressors and oncogenes, misregulating cellular differentiation and promoting cancer cell proliferation. Thus, targeting aberrant histone ubiquitination m ...[more]

PMID: 30781493

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Project description:Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient.

Dataset Information

Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer.

Publications

Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer.

Similar Datasets

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