Epigenetic regulation of ID4 in breast cancer: tumor suppressor or oncogene?

Abstract

BackgroundInhibitor of differentiation protein 4 (ID4) is a dominant negative regulator of the basic helix-loop-helix (bHLH) family of transcription factors. During tumorigenesis, ID4 may act as a tumor suppressor or as an oncogene in different tumor types. However, the role of ID4 in breast cancer is not clear where both an oncogenic and a tumor suppressor function have been attributed. Here, we hypothesize that ID4 behaves as both, but its role in breast differs according to the estrogen receptor (ER) status of the tumor.MethodsID4 expression was retrieved from TCGA database using UCSC Xena. Association between overall survival (OS) and ID4 was assessed using Kaplan–Meier plotter. Correlation between methylation and expression was analyzed using the MEXPRESS tool. In vitro experiments involved ectopic expression of ID4 in MCF-7, T47D, and MDA-MB231 breast cancer cell lines. Migration and colony formation capacity were assessed after transfection treatments. Gene expression was analyzed by ddPCR and methylation by MSP, MS-MLPA, or ddMSP.ResultsData mining analysis revealed that ID4 expression is significantly lower in ER+ tumors with respect to ER− tumors or normal tissue. We also demonstrate that ID4 is significantly methylated in ER+ tumors. Kaplan–Meier analysis indicated that low ID4 expression levels were associated with poor overall survival in patients with ER+ tumors. In silico expression analysis indicated that ID4 was associated with the expression of key genes of the ER pathway only in ER+ tumors. In vitro experiments revealed that ID4 overexpression in ER+ cell lines resulted in decreased migration capacity and reduced number of colonies. ID4 overexpression induced a reduction in ER levels in ER+ cell lines, while estrogen deprivation with fulvestrant did not induce changes neither in ID4 methylation nor in ID4 expression.ConclusionsWe propose that ID4 is frequently silenced by promoter methylation in ER+ breast cancers and functions as a tumor suppressor gene in these tumors, probably due to its interaction with key genes of the ER pathway. Our present study contributes to the knowledge of the role of ID4 in breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0542-8) contains supplementary material, which is available to authorized users.

Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

“…The data of this study, showing that Id4 may act to impede the evolution of lung cancer metastasis, are similar to those from prostate cancer [41,42], glioblastoma [44], and thyroid tumors [52]. Recently, Nasif and his colleague demonstrated that Id4 is significantly methylated in ER+ breast tumors [40]. On the other hand, Cheng et al also found that lncRNA SNHG7 could regulate the expression of Id4 via sponging miR-342-3p in pancreatic cancer [53].…”

“…Until now, the role of Id4 in cancer has remained ambiguous [39][40][41][42][43][44][45]. Although much evidence has suggested the different roles of Id4 in various cancers, the function of Id4 in lung cancer metastasis requires more careful analysis.…”

“…Cancers 2019, 11, x 11 of 18 [44], and thyroid tumors [52]. Recently, Nasif and his colleague demonstrated that Id4 is significantly methylated in ER+ breast tumors [40]. On the other hand, Cheng et al also found that lncRNA SNHG7 could regulate the expression of Id4 via sponging miR-342-3p in pancreatic cancer [53].…”

<p>Expression and Prognostic Value of Id-4 in Patients with Esophageal Squamous Cell Carcinoma</p>

“…22 The biological mechanism of Id-4 as a tumor suppressor is not understood fully. Aberrant promoter methylation of Id-4 followed by the decreased expression of Id-4 is one of the potential molecular mechanisms, which has been confirmed in prostate cancer, 23 breast cancer, 15 lung cancer, 24 colorectal cancer, 25 and lymphocytic leukemia. 19 Besides, Pankaj Sharma et found that Id-4 could heterodimerize with Id-1, −2 and −3 with consequent reactivation of DNA transcription, thus antagonizing the biological activities of such Id proteins.…”

Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma

“…Sirnes et al reported that GJC1 promoter methylation played a crucial role in colorectal cancer [38] and follicular lymphoma [39]. ID4 serves as hypermethylation gene and tumor suppressor gene in breast cancer [40,41] and acute leukemia [42,43]. ID4 promoter methylation was also correlated with the risk of prostate cancer [44,45].…”