Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

Giannopoulou, Aikaterini F.; Velentzas, Athanassios D.; Konstantakou, Eumorphia G.; Avgeris, Margaritis; Katarachia, Stamatia A.; Παπανδρεου, Νικολαοσ; Kalavros, Nikolas; Mpakou, Vassiliki; Iconomidou, Vassiliki A.; Anastasiadou, Ema; Kostakis, Ioannis K.; Papassideri, Issidora S.; Voutsinas, Gerassimos E.; Scorilas, Andreas; Stravopodis, Dimitrios J.

doi:10.3390/ijms20061291

Cited by 50 publications

(44 citation statements)

References 267 publications

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“…Thus, identifying a novel biomarker for the prognostic prediction of OC is necessary. Previously, the SIRT family has been reported to serve a critical part in the process of tumorigenesis (25)(26)(27). Each individual SIRT may act either as a tumor suppressor or an oncogene in different types of malignancies, potentially via tumor-associated signaling pathways or mitosis regulation (13,28,29).…”

Section: Discussionmentioning

confidence: 99%

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

Chen

et al. 2020

Oncol Lett

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Ovarian cancer (OC) is the fifth most frequent cause of cancer-associated mortality worldwide, and is accompanied by asymptomatic progression. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent protein deacetylases, comprising seven members (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7). Accumulating evidence has demonstrated that SIRTs act as prognostic estimators in certain types of cancer such as lung cancer, prostate cancer, gastric cancer, breast cancer and colorectal cancer. However, it remains unknown whether individual SIRTs can serve as independent prognostic factors in OC. In the present study, the Kaplan-Meier plotter online database was utilized to examine the prognostic values of SIRT mRNA expression in patients with OC. The results demonstrated that the overexpression of SIRT3, SIRT5, SIRT6 and SIRT7 mRNAs was associated with a good prognosis in patients, whereas elevated mRNA levels of SIRT1 and SIRT4 indicated poor survival in patients with OC. In addition, among the favorable predictors, SIRT3, SIRT5, SIRT6 and SIRT7 overexpression were associated with overall survival (OS), according to clinical characteristics, such as histological classification, clinical stage, pathology grade, drug therapy and tumor protein p53 mutation status in patients with OC. Similarly, SIRT4 mRNA overexpression was associated with poor OS in pathological grade III cancer. High SIRT1 and SIRT4 expression were associated with unfavorable OS at all clinical stages. Furthermore, SIRT1 and SIRT4 were negatively associated with OS in drug-treated patients. In summary, the present study demonstrated that the SIRT family is associated with the prognosis of human OC, suggesting that individual SIRTs may also act as prognostic predictors in patients.

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Section: Discussionmentioning

confidence: 99%

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

Chen

et al. 2020

Oncol Lett

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“…11,[19][20][21][22] Several HDACi (ie, vorinostat, mocetinostat, belinostat) have been studied in clinical trials of urothelial bladder cancer. 23 However, despite the clinical benefits of vorinostat, a pan-HDACi, it is reported to have serious adverse effects. Mocetinostat, class I and IV, is also compromised by severe toxicities.…”

Section: Discussionmentioning

confidence: 99%

The Histone Deacetylase Inhibitor Romidepsin Spares Normal Tissues While Acting as an Effective Radiosensitizer in Bladder Tumors in Vivo

Paillas

Then

Kilgas

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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The class I histone deacetylase inhibitor romidepsin sensitizes bladder cancer cells to ionizing radiation (IR) and delays tumor growth after IR. Treatment with romidepsin þ IR did not increase the normal tissue toxicity caused by radiation to the surrounding normal bowel incorporated in the radiation field acutely at 3.75 days after radiation or later at 29 weeks. Romidepsin treatment impaired both homologous recombination and nonhomologous end joining DNA repair pathways. Purpose: Muscle-invasive bladder cancer has a 40% to 60% 5-year survival rate with radical treatment by surgical removal of the bladder or radiation therapyebased bladder preservation techniques, including concurrent chemoradiation. Elderly patients cannot tolerate current chemoradiation therapy regimens and often receive only radiation therapy, which is less effective. We urgently need effective chemotherapy agents for use with radiation therapy combinations that are nontoxic to normal tissues and tolerated by elderly patients. Methods and Materials: We have identified histone deacetylase (HDAC) inhibitors as promising agents to study. Pan-HDAC inhibition, using panobinostat, is a good strategy for radiosensitization, but more selective agents may be more useful radiosensitizers in a clinical setting, resulting in fewer systemic side effects. Herein, we study the HDAC class I-selective agent romidepsin, which we predict to have fewer off-target effects than panobinostat while maintaining an effective level of tumor radiosensitization. Results: In vitro effects of romidepsin were assessed by clonogenic assay and showed that romidepsin was effective in the nanomolar range in different bladder cancer cells and radiosensitized these cells. The radiosensitizing effect of romidepsin was confirmed in vivo using superficial xenografts. The drug/irradiation combination treatment resulted in significant tumor growth delay but did not increase the severity of acute (3.75 days) intestinal normal tissue toxicity or late toxicity at 29 weeks.

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“…However, whether histone acetylation triggers the p19 expression in our cell culture model has not been evaluated and, therefore, remains speculative. Whether or not direct cross-communication exists between aH3/aH4 and p19, HDAC inhibitors should be considered relevant in treating patients with solid tumors [47]. Hence, combining the mTOR inhibitor everolimus with a naturally derived epigenetic drug such as SFN may provide an innovative strategy in treating bladder cancer by acetylating histones H3 and H4 and concomitantly elevating the tumor suppressor p19.…”

Section: Discussionmentioning

confidence: 99%

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

Justin

Rutz

Maxeiner

et al. 2020

IJMS

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Progressive bladder cancer growth is associated with abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, but treatment with an mTOR inhibitor has not been as effective as expected. Rather, resistance develops under chronic drug use, prompting many patients to lower their relapse risk by turning to natural, plant-derived products. The present study was designed to evaluate whether the natural compound, sulforaphane (SFN), combined with the mTOR inhibitor everolimus, could block the growth and proliferation of bladder cancer cells in the short- and long-term. The bladder cancer cell lines RT112, UMUC3, and TCCSUP were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM) alone or in combination. Cell growth, proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins were evaluated. siRNA blockade was used to investigate the functional impact of the proteins. Short-term application of SFN and/or everolimus resulted in significant tumor growth suppression, with additive inhibition on clonogenic tumor growth. Long-term everolimus treatment resulted in resistance development characterized by continued growth, and was associated with elevated Akt-mTOR signaling and cyclin-dependent kinase (CDK)1 phosphorylation and down-regulation of p19 and p27. In contrast, SFN alone or SFN+everolimus reduced cell growth and proliferation. Akt and Rictor signaling remained low, and p19 and p27 expressions were high under combined drug treatment. Long-term exposure to SFN+everolimus also induced acetylation of the H3 and H4 histones. Phosphorylation of CDK1 was diminished, whereby down-regulation of CDK1 and its binding partner, Cyclin B, inhibited tumor growth. In conclusion, the addition of SFN to the long-term everolimus application inhibits resistance development in bladder cancer cells in vitro. Therefore, sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.

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Revisiting Histone Deacetylases in Human Tumorigenesis: The Paradigm of Urothelial Bladder Cancer

Cited by 50 publications

References 267 publications

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

Associations of sirtuins with clinicopathological variables and prognosis in human ovarian cancer

The Histone Deacetylase Inhibitor Romidepsin Spares Normal Tissues While Acting as an Effective Radiosensitizer in Bladder Tumors in Vivo

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

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