Epigenetic Repression of <i>microRNA-129-2</i> Leads to Overexpression of <i>SOX4</i> Oncogene in Endometrial Cancer

Huang, Yi Wen; Liu, Joseph C.; Deatherage, Daniel E.; Luo, Jingqin; Mutch, David G.; Goodfellow, Paul J.; Miller, David S.

doi:10.1158/0008-5472.can-09-1499

Cited by 257 publications

(233 citation statements)

References 33 publications

(40 reference statements)

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“…The motifs we found hint at proteins involved at ERα/chromatin interactions at differential ERα-binding sites in endometrial tumors of tamoxifen users and nonusers. These motifs indicate a role for stem cell markers, such as SOX4 (39) and NANOG (40) in nonusers, and for members of the nuclear receptor family, including the androgen receptor, glucocorticoid, and thyroid hormone receptor in tamoxifen users.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, ERα-binding sites enriched in endometrial tumors from nonusers mostly included motifs of the forkhead domain family and the high-mobility Box family group. This last group contains well-known stem cell markers, such as sex-determining region Y-box 4 (SOX4) and Nanog homeobox (NANOG), which associate with endometrial cancer (39,40). Both groups contained motifs for leucine zipper proteins at the differential ERα-binding sites.…”

Section: Differential Erα-binding Sites In Tumors From Tamoxifen Usermentioning

confidence: 99%

See 1 more Smart Citation

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The DNA-binding sites of estrogen receptor α (ERα) show great plasticity under the control of hormones and endocrine therapy. Tamoxifen is a widely applied therapy in breast cancer that affects ERα interactions with coregulators and shifts the DNA-binding signature of ERα upon prolonged exposure in breast cancer. Although tamoxifen inhibits the progression of breast cancer, it increases the risk of endometrial cancer in postmenopausal women. We therefore asked whether the DNA-binding signature of ERα differs between endometrial tumors that arise in the presence or absence of tamoxifen, indicating divergent enhancer activity for tumors that develop in different endocrine milieus. Using ChIP sequencing (ChIP-seq), we compared the ERα profiles of 10 endometrial tumors from tamoxifen users with those of six endometrial tumors from nonusers and integrated these results with the transcriptomic data of 47 endometrial tumors from tamoxifen users and 64 endometrial tumors from nonusers. The ERα-binding sites in tamoxifen-associated endometrial tumors differed from those in the tumors from nonusers and had distinct underlying DNA sequences and divergent enhancer activity as marked by histone 3 containing the acetylated lysine 27 (H3K27ac). Because tamoxifen acts as an agonist in the postmenopausal endometrium, similar to estrogen in the breast, we compared ERα sites in tamoxifen-associated endometrial cancers with publicly available ERα ChIP-seq data in breast tumors and found a striking resemblance in the ERα patterns of the two tissue types. Our study highlights the divergence between endometrial tumors that arise in different hormonal conditions and shows that ERα enhancer use in human cancer differs in the presence of nonphysiological endocrine stimuli.E strogen receptor α (ERα) is a steroid hormone receptor that behaves as a transcription factor by interacting with the DNA. The DNA-binding profile (cistrome) of ERα is dependent on context and tissue type (1). The hormonal environment of the cell greatly influences this cistrome because estrogen activates ERα by binding its ligand-binding domain. Upon activation, ERα's structural conformation changes to interact with cofactors at the DNA (2) and to regulate a transcriptional program that drives cell proliferation (3). Hence, the hormonal environment modulates the ERα cistrome and thereby rewires downstream effects.Endocrine therapies, as exemplified by tamoxifen, manipulate the DNA-binding capacities of the steroid hormone receptor ERα. Tamoxifen, a small-molecule inhibitor that competes with estrogens to bind ERα, is a major endocrine agent used in treating ERα-positive breast cancer patients. Studies in the breast cancer cell line MCF-7 show that prolonged tamoxifen exposure shifts the ERα cistrome, which consequently changes gene expression (4-6).Tamoxifen is a well-known selective estrogen receptor modulator (SERM) with tissue-selective physiological action. Early reports on tamoxifen's effects on transplanted MCF-7 cells in athymic mice revealed decreased tumor c...

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Section: Discussionmentioning

confidence: 99%

Section: Differential Erα-binding Sites In Tumors From Tamoxifen Usermentioning

confidence: 99%

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Droog

Nevedomskaya

Dackus

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[14][15][16] This may reflect a heterogeneity of tumor samples and the use of different platforms for miRNA detection may account for the differing results. 17 In spite of some discordance, however, 15,16 some common dysregulated miRNAs have been revealed. Dysregulation of miR-182, miR-204, miR-205 and miR-449 identified here is consistent with Wu's report.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Chung

Lau

Cheung

et al. 2011

Intl Journal of Cancer

155

128

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TXMicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. Differential miRNA expression signatures have been documented in many human cancers but the role of miRNAs in endometrioid endometrial cancer (EEC) remains poorly understood. This study identifies significantly dysregulated miRNAs of EEC cells, and characterizes their impact on the malignant phenotype. We studied the expression of 365 human miRNAs using Taqman low density arrays in EECs and normal endometriums. Candidate differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of highly dysregulated miRNAs was examined in vitro through the effect of anti-/pre-miRNA transfection on the malignant phenotype. We identified 16 significantly dysregulated miRNAs in EEC and 7 of these are novel findings with respect to EEC. Antagonizing the function of miR-7, miR-194 and miR-449b, or overexpressing miR-204, repressed migration, invasion and extracellular matrix-adhesion in HEC1A endometrial cancer cells. FOXC1 was determined as a target gene of miR-204, and two binding sites in the 3 0 -untranslated region were validated by dual luciferase reporter assay. FOXC1 expression was inversely related to miR-204 expression in EEC. Functional analysis revealed the involvement of FOXC1 in migration and invasion of HEC1A cells. Our results present dysfunctional miRNAs in endometrial cancer and identify a crucial role for miR-204-FOXC1 interaction in endometrial cancer progression. This miRNA signature offers a potential biomarker for predicting EEC outcomes, and targeting of these cancer progression-and metastasis-related miRNAs offers a novel potential therapeutic strategy for the disease.Endometrial cancer is a common cause of gynecological cancer death. The most dominant subtype, endometrioid endometrial cancer (EEC), accounts for >80% of this cancer. Menopause and unopposed estrogenic stimulation are typical risk factors. Patients are generally treated with surgery, radiation, chemotherapy or hormone therapy. Patients with early stage disease have 5-year survival rates over 80%, however, about 15-20% develop metastasis. 1 These patients and those with advanced stage disease or recurrence have poor prognosis due to limitation of effective treatment. 2 Understanding the pathogenesis of this disease may provide insights for the development of novel therapeutic strategies.MicroRNAs (miRNAs) are small noncoding RNA molecules of 19-24 nucleotides that regulate gene expression posttranscriptionally through imperfect base pairing with the 3 0 -untranslated region (3 0 UTR) of target mRNAs, causing transcript degradation and translational inhibition. 3 Approximately 20-30% of all genes are targeted by miRNAs and a single miRNA may target as many as 200 genes. 4 In human cancers, >50% of the miRNA genes are located in chromosomal fragile sites, minimal regions containing loss of heterozygosity, minimal amplicons or common breakpoint regions. 5 DNA ...

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“…Whereas DNA hypomethylation may contribute to the tumorigenic process by inducing chromosomal instability and reactivation of transposons and oncogenes, hypermethylation of CpG islands may result in the silencing of tumor-suppressor genes, a hallmark during cancer onset and progression (Feinberg and Vogelstein, 1983;Gama-Sosa et al, 1983;Fraga and Esteller, 2005;Weber et al, 2005). More recently, changes in the methylation pattern of DNA regions coding for micro-RNAs (miRs) that modulate the expression of oncogenes or tumor suppressors have been reported (Datta et al, 2008;Huang et al, 2009;Pallasch et al, 2009). Inversely, it has been observed that oncofusion proteins can epigenetically silence miRs that are critically involved in lineage specification (Fazi et al, 2007).…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Epigenetic Repression of microRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer

Cited by 257 publications

References 33 publications

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Estrogen receptor α wields treatment-specific enhancers between morphologically similar endometrial tumors

Dysregulation of microRNA‐204 mediates migration and invasion of endometrial cancer by regulating FOXC1

Towards novel paradigms for cancer therapy

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