Epigenetic regulation of RhoB loss of expression in lung cancer

Tovar, Daniel; He, Biao; Nieto-Acosta, Jacobo; Marty-Detraves, Claire; Clanet, Carine; Pradines, Anne; Jablons, David M.; Favre, Gilles

doi:10.1186/1471-2407-7-220

Cited by 34 publications

(32 citation statements)

References 26 publications

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“…Moreover, RhoB loss could induce Rac1-dependent mesenchymal cell invasion in lung cells through the control of PP2A activity, 29 and promote the invasion of human bronchial cells via the activation of AKT1. 42 Furthermore, Mazieres et al 43 also reported that the loss of RhoB expression was induced via epigenetic regulation by histone deacetylation in lung cancer, whereas we found that LSD1 recruited by DUXAP8-mediated histone demethylation also contributed to RHOB loss of expression in NSCLC cells. Interestingly, rescue experiments demonstrated that the pseudogene DUXAP8 exerts oncogenic function in a manner partly dependent on the repression of RHOB and EGR1 expression in NSCLC cells.…”

Section: Discussioncontrasting

confidence: 48%

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

et al. 2017

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Recently, the non-protein-coding functional elements in the human genome have been identified as key regulators in postgenomic biology, and a large number of pseudogenes as well as long non-coding RNAs (lncRNAs) have been found to be transcribed in multiple human cancers. However, only a small proportion of these pseudogenes has been functionally characterized. In this study, we screened for pseudogenes associated with human non-small-cell lung cancer (NSCLC) by comparative analysis of several independent datasets from the GEO. We identified a transcribed pseudogene named DUXAP8 that is upregulated in tumor tissues. Patients with higher DUXAP8 expression exhibited shorter survival, suggesting DUXAP8 as a new candidate prognostic marker for NSCLC patients. Knockdown of DUXAP8 impairs cell growth, migration, and invasion, and induces apoptosis both in vitro and in vivo. Mechanistically, DUXAP8 represses the tumor suppressors EGR1 and RHOB by recruiting histone demethylase LSD1 and histone methyltransferase EZH2, thereby promoting cell proliferation, migration, and invasion. These findings indicate that the pseudogene DUXAP8 may act as an oncogene in NSCLC by silencing EGR1 and RHOB transcription by binding with EZH2 and LSD1, which may offer a novel therapeutic target for this disease.

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Section: Discussioncontrasting

confidence: 48%

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

et al. 2017

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“…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: 99%

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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“…In the case of RhoE, no CpG island was found in its promoter. However, the promoter region of CAR (33) and RhoB (13) contains CpG islands, and DNA methylation still does not seem to play a role in controlling their gene expression. The reason for this phenomenon is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…One of two proteins is RhoB, which was reported to act as a suppressor in many cancers (12). Interestingly, histone deacetylation modification, rather than DNA methylation, is the cause of its down-regulation in lung cancer (13). The other protein studied is Rnd1, which was also reported to be down-regulated by histone deacetylation in gastric cancer (14).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic modification of RhoE expression in gastric cancer cells

Chen

Zhou²,

Li³

et al. 2010

Oncol Rep

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Abstract. RhoE is a unique member of Rho family of GTPases without detectable intrinsic GTPase activity. Our previous study showed that RhoE is a tumor suppressor gene and its expression is down-regulated in gastric cancer. However, the mechanism underlying the down-regulated expression of RhoE in gastric cancer has not been elucidated yet. In the present study, the effect of epigenetic modification on the RhoE expression in gastric cancer cells was investigated. The mRNA and protein expression of RhoE were detected by real-time RT-PCR and Western blotting, respectively. Results showed RhoE was significantly down-regulated in three gastric cancer cell lines. A promoter (2980 bp) of RhoE and its five truncated mutants were cloned into vector pGL-3Basic for the activity analysis by luciferase reporter assay. Treatment with trichostatin A, a histone deacetylation inhibitor, enhanced not only the activity of RhoE promoter, but also the mRNA and protein expression of RhoE in three gastric cancer cell lines, whereas treatment with 5-Aza-2'-deoxycytidine, a DNA methylation inhibitor, affected neither RhoE promoter activity nor RhoE expression. No synergistic effect was observed in cells treated with both drugs. Our results suggested that RhoE expression in gastric cancer cells was regulated by histone deacetylation, but not by DNA methylation, at the epigenetic level.

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Epigenetic regulation of RhoB loss of expression in lung cancer

Abstract: Background: RhoB is down-regulated in most lung cancer cell lines and tumor tissues when compared with their normal counterparts. The mechanism of this loss of expression is not yet deciphered.

Cited by 34 publications

References 26 publications

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

RETRACTED: The Pseudogene DUXAP8 Promotes Non-small-cell Lung Cancer Cell Proliferation and Invasion by Epigenetically Silencing EGR1 and RHOB

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

Epigenetic modification of RhoE expression in gastric cancer cells

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