Histones: Controlling Tumor Signaling Circuitry

Martins, Manoela Domingues; Castilho, Rogerio M.

doi:10.4172/2157-2518.s5-001

Cited by 15 publications

(11 citation statements)

References 140 publications

(160 reference statements)

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“…Interestingly, mucous-like tumor cells are also hypoacetylated. Indeed, the level of histone acetylation correlates with the transcriptional activity of the cell [61, 62]. Histone acetylation is associated with increased transcription of genes involved in differentiation, and histone deacetylation is associated with reduced gene transcription and/or activation of stem cell-associated genes.…”

Section: Discussionmentioning

confidence: 99%

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

et al. 2016

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Mucoepidermoid carcinoma (MEC) is the most common malignancy of salivary glands. The response of MEC to chemotherapy is unpredictable, and recent advances in cancer biology suggest the involvement of cancer stem cells (CSCs) in tumor progression and chemoresistance and radioresistance phenotype. We found that histone acetyltransferase inhibitors (HDACi) were capable of disrupting CSCs in MEC. Furthermore, administration of HDACi prior to Cisplatin (two-hit approach) disrupts CSCs and sensitizes tumor cells to Cisplatin. Our findings corroborate to emerging evidence that CSCs play a key role in tumor resistance to chemotherapy, and highlights a pharmacological two-hit approach that disrupts tumor resistance to conventional therapy.

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Section: Discussionmentioning

confidence: 99%

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

et al. 2016

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“…HDACi represents a growing class of anticancer agents that regulates gene expression through histone acetylation modulation. In several cancers, treatment with HDACi results in differentiation, cell cycle arrest, apoptosis, and decreasing of angiogenesis [ 26 , 178 , 179 ]. Through hyperacetylation of histone and non-histone targets, HDACi enables the reestablishment of cellular acetylation homeostasis, and restores normal expression and function of several proteins that may reverse cancer initiation, progression, and therapy resistance [ 52 ].…”

Section: Epigenetic Drugs and Hnscc Therapymentioning

confidence: 99%

“…The most promising HDACi results were seen when it was combined with other therapeutic regimens, including its combination with radio and chemotherapy, which resulted in synergistic or additive effects. Indeed, HDACi is mostly effective against HNSCC when administrated with other therapeutic agents [ 178 , 180 , 181 ]. Treatment using combined Trichostatin A (TSA) and all-trans-retinoic acid (ATRA), synergistically increased the growth-inhibitory effect, and strongly induced transcriptional activation of target genes, which restored tumor sensitivity to retinoic acid in HNSCC cell lines [ 182 ].…”

Section: Epigenetic Drugs and Hnscc Therapymentioning

confidence: 99%

Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

Castilho

Squarize

Almeida

2017

IJMS

137

121

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Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

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“…Histone modifications occur by acetylation, methylation, ubiquitination, phosphorylation, and sumoylation to directly influence DNA packaging and increase transcription. 1 , 2 Histone modifications are detected during normal cellular plasticity in neurons and lymphocytes and play a major role in tumor behavior. 3 – 5 In cancer cells, histone modifications dynamically promote transcription of prosurvival genes and silence tumor suppressor genes to support the deregulated cancer physiology.…”

Section: Introductionmentioning

confidence: 99%

“…The pattern of histone modifications determines chromatin status (euchromatin or heterochromatin), the accessibility of DNA to nuclear factors, and ultimately transcription. 2 , 22 Alterations in chromatin structure due to histone modifications have been correlated with gene expression, the cell cycle, DNA replication and damage, DNA repair, and chromosome stability. 2 , 23 Among all histone modifications, the process of global chromatin remodeling driven by acetylation of histones is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy

et al. 2015

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Epigenetics refers to changes in cell characteristics that occur independently of modifications to the deoxyribonucleic acid (DNA) sequence. Alterations mediated by epigenetic mechanisms are important factors in cancer progression. Although an exciting prospect, the identification of early epigenetic markers associated with clinical outcome in premalignant and malignant disorders remains elusive. We examined alterations in chromatin acetylation in oral lichen planus (OLP) with distinct clinical behavior and compared the alterations to the levels of DNA double-strand breaks (DSBs). We analyzed 42 OLP patients, who had different responses to therapy, for acetyl-histone H3 at lys9 (H3K9ac), which is associated with enhanced transcription and nuclear decondensation, and the presence of DSBs, as determined by accumulation of phosphorylated γH2AX foci. Patients with high levels of H3K9ac acetylation failed to respond to therapy or experienced disease recurrence shortly after therapy. Similar to H3K9ac, patients who responded poorly to therapy had increased accumulation of DNA DSB, indicating genomic instability. These findings suggest that histone modifications occur in OLP, and H3K9ac and γH2AX histones may serve as epigenetic markers for OLP recurrence.

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Histones: Controlling Tumor Signaling Circuitry

Cited by 15 publications

References 140 publications

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

Epigenetic Modifications and Head and Neck Cancer: Implications for Tumor Progression and Resistance to Therapy

Epigenetic Modifications and Accumulation of DNA Double-Strand Breaks in Oral Lichen Planus Lesions Presenting Poor Response to Therapy

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