Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer

Jeusset, Lucile M.; McManus, Kirk J.

doi:10.3390/cells8020165

Cited by 52 publications

(36 citation statements)

References 144 publications

(172 reference statements)

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“…Epigenetic regulation of EMT (Figure 4) has mainly focused on histone methylation/acetylation, with additional studies detailing the roles of other histone modifications such as phosphorylation (141)(142)(143), ubiquitination (144)(145)(146), citrullination (85,(147)(148)(149), SUMOylation (150)(151)(152), and biotinylation (153) in EMT. Histone modifying enzymes are dynamic and diverse.…”

Section: Epigenetic Mechanisms Involved In Emt-room To Explorementioning

confidence: 99%

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Lavin

Tiwari

2020

Front. Oncol.

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Epithelial to mesenchymal transition (EMT) is the process whereby a polarized epithelial cell ceases to maintain cell-cell contacts, loses expression of characteristic epithelial cell markers, and acquires mesenchymal cell markers and properties such as motility, contractile ability, and invasiveness. A complex process that occurs during development and many disease states, EMT involves a plethora of transcription factors (TFs) and signaling pathways. Whilst great advances have been made in both our understanding of the progressive cell-fate changes during EMT and the gene regulatory networks that drive this process, there are still gaps in our knowledge. Epigenetic modifications are dynamic, chromatin modifying enzymes are vast and varied, transcription factors are pleiotropic, and signaling pathways are multifaceted and rarely act alone. Therefore, it is of great importance that we decipher and understand each intricate step of the process and how these players at different levels crosstalk with each other to successfully orchestrate EMT. A delicate balance and fine-tuned cooperation of gene regulatory mechanisms is required for EMT to occur successfully, and until we resolve the unknowns in this network, we cannot hope to develop effective therapies against diseases that involve aberrant EMT such as cancer. In this review, we focus on data that challenge these unknown entities underlying EMT, starting with EMT stimuli followed by intracellular signaling through to epigenetic mechanisms and chromatin remodeling.

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Section: Epigenetic Mechanisms Involved In Emt-room To Explorementioning

confidence: 99%

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Lavin

Tiwari

2020

Front. Oncol.

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“…So far most reported ubiquitin histone molecules are of H2A and H2B. Lower H2AK127ub1 and H2BK120ub1level associated with breast cancer [165][166][167]. USP22 (Ubiquitin specific protease 22) is an ubiquitin enzyme, which removes ubiquitin molecule from histone H2A, and H2B variants [168].…”

Section: Ubiquitinationmentioning

confidence: 99%

A three layered histone epigenetics in breast cancer metastasis

2020

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Thanks to the advancement in science and technology and a significant number of cancer research programs being carried out throughout the world, the prevention, prognosis and treatment of breast cancer are improving with a positive and steady pace. However, a stern thoughtful attention is required for the metastatic breast cancer casesthe deadliest of all types of breast cancer, with a character of relapse even when treated. In an effort to explore the less travelled avenues, we summarize here studies underlying the aspects of histone epigenetics in breast cancer metastasis. Authoritative reviews on breast cancer epigenetics are already available; however, there is an urgent need to focus on the epigenetics involved in metastatic character of this cancer. Here we put forward a comprehensive review on how different layers of histone epigenetics comprising of histone chaperones, histone variants and histone modifications interplay to create breast cancer metastasis landscape. Finally, we propose a hypothesis of integrating histone-epigenetic factors as biomarkers that encompass different breast cancer subtypes and hence could be exploited as a target of larger population.

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“…Studies investigating the development of inhibitors of atypical histone modifications, such as citrullination, phosphorylation, sumoylation, ubiquitylation, and ribosylation; are needed because these modifications are also known to regulate gene transcription and contribute to cancer progression ( 175 – 178 ). The mechanisms outlined in this review offer not only a rationale for successful combinations and mechanisms, but also identify indications for their use in specific patients based on the markers being modulated, in line with the advancements in personalized medicine.…”

Section: Discussionmentioning

confidence: 99%

Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

2020

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The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.

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Developing Targeted Therapies That Exploit Aberrant Histone Ubiquitination in Cancer

Cited by 52 publications

References 144 publications

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

A three layered histone epigenetics in breast cancer metastasis

Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer

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