Reactivation of Suppressed RhoB is a Critical Step for the Inhibition of Anaplastic Thyroid Cancer Growth

Marlow, Laura A.; Reynolds, Lisa A.; Cleland, Alan S.; Cooper, Simon; Gumz, Michelle L.; Kurakata, Shinichi; Fujiwara, Kôsaku; Zhang, Ying; Sebo, Thomas; Grant, Clive S.; McIver, Bryan; Wadsworth, J. Trad; Radisky, Derek C.; Smallridge, Robert C.; Copland, John A.

doi:10.1158/0008-5472.can-08-3718

Cited by 67 publications

(54 citation statements)

References 41 publications

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“…Therefore, histone modifications or other transcriptional regulatory mechanism may be responsible for the loss of RhoB expression. Preclinical data suggest increased histone acetylation at the RhoB promoter region results in its reexpression in lung carcinoma and anaplastic thyroid cancer (30,34). In our study, the combination treatment resulted in significant histone H3 acetylation at the promoter region of RhoB gene compared with romidepsin alone suggesting histone acetylation is responsible for transcriptional activity of RhoB, which is further enhanced by the hypomethylating agent azacitidine.…”

Section: Discussionsupporting

confidence: 54%

“…This might be due to the fact that DNA hypomethylation results in a more accessible chromatin for histone acetylation or due to DNA hypomethylation-independent effects of azacitidine that could contribute to the synergistic effects of the combination. It is suggested that RhoB promotes cell-cycle arrest by controlling the expression of cell-cycle regulators such as p21 (34). We observed an upregulation of p21 in cell lines and tumor cells derived from S ezary syndrome patients.…”

Section: Discussionmentioning

confidence: 51%

“…In addition, it did not demonstrate any differential methylation of RhoB promoter region under the combination treatment compared with single-agent or untreated cells (data not shown). HDAC inhibitors have been shown to reactivate RhoB expression in lung (32), ovarian (33), and thyroid cancer (34). In Fig.…”

Section: Romidepsin and Azacitidine Combination Treatment Results In mentioning

confidence: 95%

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Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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Purpose: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignancies that despite available therapies commonly relapse. The emergence of combination epigenetic therapies in other hematologic malignancies have made investigation of such combinations in CTCL a priority. Here, we explore the synergistic antiproliferative effects of romidepsin, an HDAC inhibitor, and azacitidine, a demethylating agent, combination in CTCL.Experimental Design: The growth inhibition under combination treatment and single agent was explored by the MTT cell viability assay and the Annexin V/propidium iodide (PI) apoptosis assay in different CTCL cell lines and tumor cells derived from S ezary syndrome patients. Quantitative analysis of a dose-effect relationship of romidepsin and azacitidine was done by the CompuSyn software. Investigation of mechanism of action was performed by flow cytometry, immunoblotting, qRT-PCR arrays, and chromatin immunoprecipitation. Global CpG methylation sequencing was utilized to study genome methylation alteration under the treatment modalities.Results: The combination of romidepsin and azacitidine exerts synergistic antiproliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines and tumor cells derived from S ezary syndrome patients. We identified genes that were selectively induced by the combination treatment, such as the tumor suppressor gene RhoB that is linked to enhanced histone acetylation at its promoter region in parallel with pronounced expression of p21. Global CpG methylation sequencing in a CTCL cell line and tumor cells demonstrated a subset of genes with a unique change in methylation profile in the combination treatment.Conclusions: The synergistic antiproliferative effects of romidepsin and azacitidine combination treatment justify further exploration in clinical trials for advanced CTCL.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 51%

Section: Romidepsin and Azacitidine Combination Treatment Results In mentioning

confidence: 95%

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Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Rozati

Cheng

Widmer

et al. 2016

Clinical Cancer Research

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“…It has also been shown to sensitize a human anaplastic thyroid cancer (ATC) cell line to doxorubicin (Kitazono et al 2002). Depsipeptide induces RhoB activity, which leads to upregulated p21 expression that attenuates cell proliferation (Marlow et al 2009). Valproic acid strongly suppresses the growth of poorly differentiated thyroid cancer cell lines by inducing apoptosis and cell cycle arrest (Catalano et al 2005(Catalano et al , 2006.…”

Section: Rarb2mentioning

confidence: 99%

Epigenetics of thyroid cancer and novel therapeutic targets

Russo¹,

Damante²,

Puxeddu³

et al. 2011

Journal of Molecular Endocrinology

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An increasing body of evidence suggests that epigenetic changes (DNA methylation, remodeling and post-translational modification of chromatin) play important roles in thyroid tumorigenesis, as a result of their effects on tumor-cell differentiation and proliferation. Epigenetic silencing of various thyroid-specific genes has been detected in thyroid tumors. These changes can diminish the tumor's ability to concentrate radioiodine, which dramatically reduces treatment options. Epigenetic changes in tumor-promoting and tumor-suppressor genes also contribute to the dysregulation of thyrocyte growth and other aspects of tumorigenesis, such as apoptosis, motility and invasiveness. We provide a brief overview of the mechanisms underlying epigenetic regulation of gene expression and the current methods used to investigate it. This is followed by a review of the principal epigenetic alterations detected in thyroid cancer cells, epigenetic strategies for treating thyroid cancers and data from preclinical and clinical studies (some still underway) on the use in this setting of demethylating agents and histone deacetylase inhibitors.

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“…PPAR-g plays a variety of roles in adipose cell differentiation, modulation of metabolism, and the inflammatory response (2,3). The protein interacts with and/or regulates multiple signaling pathways, including those associated with p21Cip1 (4,5) and p27 (6,7) to regulate the cell cycle, with nuclear factor kappa b (8) to reduce the expression of cytokines such as interleukin-6, and interleukin-8, and with cyclooxygenase-2 and prostaglandin E2 to suppress inflammation (9,10). Genetic studies have indicated that PPAR-g functions as a tumor suppressor in a variety of tissues, including the breast (11), prostate (12), and colon (13).…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Agonists of PPAR-γ Exert Therapeutic Effects in Esophageal Cancer

et al. 2014

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The transcription factor PPAR-g plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-g agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-g agonist that selectively activates PPAR-g target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-g status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-g was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-g expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-g agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, the combination of efatutazone with the antiepithelial growth factor receptor antibody cetuximab synergized to negatively regulate the phosphoinositide 3-kinase-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC. Cancer Res; 74(2); 575-85. Ó2013 AACR.

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Reactivation of Suppressed RhoB is a Critical Step for the Inhibition of Anaplastic Thyroid Cancer Growth

Cited by 67 publications

References 41 publications

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Romidepsin and Azacitidine Synergize in their Epigenetic Modulatory Effects to Induce Apoptosis in CTCL

Epigenetics of thyroid cancer and novel therapeutic targets

Small Molecule Agonists of PPAR-γ Exert Therapeutic Effects in Esophageal Cancer

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