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Published in final edited form as: Biochimie. 2019 Mar 29;162:8–14. doi: 10.1016/j.biochi.2019.03.019

SOX11 hypermethylation as a tumor biomarker in endometrial cancer

Tianjiao Shan 1,2, Denise S Uyar 1, Li-Shu Wang 3, David G Mutch 4, Tim H-M Huang 5, Janet S Rader 1, Xiugui Sheng 2,6,*, Yi-Wen Huang 1,*
PMCID: PMC6561798  NIHMSID: NIHMS1525756  PMID: 30935961

Abstract

We previously reported that SOX4 is overexpressed in endometrial cancer and that it partially contributes to hypermethylation of miR-129–2 and miR-203. The current study seeks to identify methylation and expression levels of the SOX gene family in endometrial carcinomas. Methylation levels of the 16 SOX gene family members were measured by combining bisulfite restriction analysis (COBRA), MassARRAY, and pyrosequencing assays of cell lines and endometrial cancer samples. Gene expression was determined by RT-qPCR. The methylation level of the SOX11 locus was correlated with clinicopathologic factors in primary endometrial tumors and in TCGA endometrial cohort. It was also examined in DNA of serum and endometrial specimens from a longitudinal cohort of early stage endometrial cancer patients. COBRA assays indicated that hypermethylation of SOX1, SOX2, SOX11, SOX14, SOX15, SOX17, and SOX18 was present in endometrial cancer cell lines and not in the normal control. SOX11 expression was reactivated only by a DNA methylation inhibitor. Moreover, aberrant DNA methylation of SOX11 was detected in the majority of endometrioid endometrial carcinomas (n=114) and none of the 22 adjacent normal endometrial samples (P<0.0001). The methylation status of SOX11 associated significantly with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.0001), and this finding was validated in TCGA endometrial cohort. Furthermore, SOX11 was not hypermethylated in serum DNA from early stage endometrial cancer patients. This study found that hypermethylation of SOX11 is common in endometrial carcinomas and strongly associates with microsatellite instability and MLH1 methylation.

Keywords: Endometrial carcinoma, DNA methylation, SOX11, biomarker, epigenetics

1. Introduction

Uterine cancer is the fourth most common cancer in U.S. women, accounting for about 7% of all female cancer diagnoses. Epithelial endometrial cancer accounts for about 90% of total uterine cancer cases[1], and it can be divided into different types. The most common is low-grade endometrioid endometrial cancer (EEC). The others, which can be classified as poorly differentiated or high-grade, include papillary serous carcinoma, clear-cell carcinoma, undifferentiated carcinoma, and high grade endometrioid carcinoma.

The Sry-related high-mobility group (HMG) box (SOX) genes are a transcription factor family comprising 20 members in the human genome. The SOXC members—SOX4, SOX11, and SOX12—are highly conserved throughout vertebrate evolution and may have redundant functions [2]. Overexpression of SOX4 has been found in many cancers, including breast, bladder, gastric, lung, prostate, and endometrial cancers [3, 4]. In the latter, we found that repression of miR-129–2 and miR-203 by DNA hypermethylation correlated with overexpression of SOX4 [4, 5]. Subsequent demethylation by pharmacologic regimens and restoration by transfection with miR-129–2 and miR-203 resulted in partial downregulation of SOX4 expression. Inhibition of SOX4 expression by siRNA attenuated endometrial cancer cell growth [4].

Because the SOX family is highly conserved and could be functionally redundant and because SOX4 is overexpressed in endometrial cancer [4], we hypothesized that other SOX family members could lose gene expression by DNA hypermethylation. In the current study, a survey of methylation levels in the CpG islands of multiple SOX genes revealed hypermethylation in endometrial cancer cell lines. Gene expression of those loci could be reactivated by a combination of DNA methylation and histone deacetylase inhibitors, but SOX11 was mainly suppressed by DNA methylation. SOX11 hypermethylation was found in endometrial cancer subtypes, both low-grade EEC and high-grade tumors, and it associated with MLH1 methylation and microsatellite instability.

2. Materials and methods

2.1. Clinical specimens

Specimens from 148 women were obtained from Washington University in St. Louis (WUSTL), The Ohio State University (OSU) [4], or the Medical College of Wisconsin (MCW). The WUSTL and OSU cohorts provided 114 endometrioid endometrial carcinomas (EEC) and 22 adjacent normal endometrial specimens from women with non-endometrial cancer. The MCW cohort included specimens from 12 early stage endometrial cancer patients. Participants consented to molecular analyses and any follow-up studies. Human subject protocols were approved by the committees at WUSTL, OSU, and MCW. Specimen confirmation, clinical characteristics, and genomic DNA extraction have been described previously [4–6].

2.2. Cell culture, treatments, and RT-qPCR

Human endometrial cancer cell lines, AN3CA, HEC1A, Ishikawa, KLE, RL95–2, and SK-UT-1B, were used in this study and authenticated by short tandem repeat [4, 5]. For epigenetic studies, these cells were treated with 5-aza-2′-deoxycytidine (DAC, 5 mM, Sigma-Aldrich, St. Louis, MO) for 48 h and/or with trichostatin A (TSA, 0.5 mM, Sigma-Aldrich) for 24 h. RNA from vehicle- or regimen-treated cells was isolated as described previously [4]. Total RNA (1 μg) underwent reverse transcription with iScript RT Supermix (Bio-Rad). PCR was performed as described previously [4, 5] with iTaq Universal SYBR Green Supermix (Bio-Rad). SOX primer sequences are described in Supplementary Table 1. The relative expression of a gene of interest was calculated by comparing the threshold cycle (Ct) of the gene to the Ct of GAPDH (a housekeeping gene).

2.3. Combined bisulfite restriction analysis (COBRA)

As delineated previously [4, 5] and following the manufacturer’s recommended protocol, genomic DNA isolated from primary human endometrial specimens and serum was converted with bisulfite, using the EZ DNA Methylation kit (Zymo Research, Irvine, CA). Primer sequences for DNA methylation are presented in Supplementary Table 2.

2.4. MassARRAY analysis

To quantify methylation levels of the SOX11 islands in the clinical samples, the high-throughput MassARRAY platform (Sequenom) was used as described previously [4]. Methylation data of individual units (one to three CpG sites per unit) were generated by EpiTyper software (Sequenom). Sequences for MassARRAY primers are displayed in Supplementary Table 3.

2.5. Bisulfite pyrosequencing

The PyroMark MD system (Qiagen, Valencia, CA) was utilized to perform bisulfite pyrosequencing according to the manufacturer’s protocol. Two sets of primers were designed by PyroMark Assay Design (Qiagen) and purchased from Thermo Fisher; the oligonucleotide sequences are presented in Supplementary Table 4. Methylation levels were quantified using PyroMark software (Qiagen).

2.6. Statistical analyses

Gene expression in human endometrial cancer cells and methylation levels in primary endometrial tumors and adjacent normal tissues were compared by using an unpaired t-test with Welch’s correction and not assuming equal standard deviation. All statistical analyses were two-sided, and a P value <0.05 was considered significant. All tests were performed using GraphPad Prism 8 software (GraphPad software, La Jolla, CA).

3. Results

3.1. Multiple members of the SOX family are hypermethylated in endometrial cancer cells

There are 20 members of the SOX family in the human genome. We investigated 16 SOXs that have CpG islands located in the 5’-flanking regions (Supplementary Fig. 1). All 16 SOX loci were evaluated by 1–3 primer sets, using COBRA assays in six endometrial cancer cell lines (AN3CA, HEC1A, Ishikawa, KLE, RL95–2, and SK-UT-1B) and a pooled sample (N) that we obtained by mixing two cancer-free endometria (Fig. 1 and Supplementary Fig. 1). Four (SOX4, SOX9, SOX12, and SOX13) of 16 SOX loci were not methylated in 6 endometrial cancer cell lines. In contrast, 12 of 16 SOX genes were hypermethylated in some or all of 6 endometrial cancer cell lines, as shown in Supplementary Fig. 1 and summarized in Fig. 1a. However, because hypermethylation of SOX3, SOX7, SOX8, and SOX30 was also detected in the normal sample (Fig. 1a), these loci were not evaluated further. COBRA assays detected hypermethylation of SOX11 in 5 of 6 endometrial cancer cell lines and 4 of 5 primary endometrial tumors but not in the normal control (Figs. 1b–c).

Fig. 1. SOX11 is hypermethylated in endometrial cancer cells.

Fig. 1

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(a) Summary by COBRA of the methylation status of the SOX gene family in endometrial cancer cell lines (from left to right: AN3CA, HEC1A, Ishikawa, KLE, RL95–2, and SK-UT-1B) and one normal (N) pooled sample derived from two noncancerous endometria as a negative control. Black and white circles: 100% and 0% methylation. Gray circles: methylated. (b) Diagram of the SOX11 locus and relative locations of methylation assays. (c) Methylation levels of SOX11 in endometrial cancer cell lines, as revealed by COBRA analysis. SssI: methylated positive control; N: normal endometrium; +, AciI: restriction enzyme added; -: without AciI; u: unmethylated; and m: methylated. C, Methylated SOX11 in primary endometrial tumors as determined by COBRA assays. *: methylated.

3.2. Reactivation of SOX11 by DNA methylation inhibitor in endometrial cancer cells

Because hypermethylation of SOX1, SOX2, SOX9, SOX11, SOX14, SOX15, SOX17, and SOX18 was observed in endometrial cancer cell lines (Fig. 1a) and the 5′-ends of these loci have a canonical CpG island (Fig. 1 and Supplementary Fig. 1), we determined whether these SOX loci can be reactivated in endometrial cancer cell lines. When these cancer cells were treated with a demethylating agent (DAC), a histone deacetylase inhibitor (TSA), or a combination of DAC and TSA, reactivation of all 8 SOX loci was observed in some or all of 6 endometrial cancer cell lines (Fig. 2). Expression levels of SOX11 were increased only by DAC in 5 of the 6 cell lines, suggesting that silencing SOX11 in endometrial cancer cells is primarily mediated through hypermethylation. Other SOX loci were repressed by both DNA hypermethylation and histone deacetylases.

Fig. 2. Relative expression levels of SOX family genes in endometrial cancer cells after treatment with DAC and/or TSA.

Fig. 2.

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Gene expression was determined by RT-qPCR and compared to untreated controls. GAPDH was used as an internal control gene. Error bar: SD; *: P<0.05 compared with untreated control of the same cell type.

3.3. Methylation of SOX11 correlates significantly with microsatellite instability (MSI) and MLH1 DNA methylation

To determine whether SOX11 is hypermethylated in primary endometrial tissues, we performed MassARRAY analysis (Fig. 1b). The methylation levels of SOX11 were examined in 114 primary EEC tumor samples and 22 samples of normal endometria (cancer-free). The methylation level of each CpG unit was quantitated, as shown in Fig. 3a. To determine the difference between the tumor and the normal groups, the average methylation levels in all the measured CpG sites in each specimen were grouped and compared. Hypermethylation of SOX11 was identified in more than 81.5% of the clinical EEC tumors but was not seen in the normal control (non-cancerous endometrium, P<0.0001; Fig. 3b). This finding is reported for the first time. Extensive DNA methylation of SOX11 significantly associated with tumor grade (P<0.001), MSI status (P<0.0001), and MLH1 hypermethylation (P<0.0001) (Figs. 3c–e).

Fig. 3. Methylation of the SOX11 CpG island and clinicopathologic covariates in primary endometrioid endometrial carcinomas (EECs).

Fig. 3.

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(a) Methylation profiles of SOX11 in 22 adjacent normal endometrial tissues and 114 primary tumors determined by MassARRAY analysis. (b) Dot plots demonstrating SOX11 hypermethylation in EEC tumors. (c–e) Dot plots indicating that methylation levels of SOX11 correlate with grade, MSI status, and MLH1 methylation. m: MLH1 methylated; u: MLH1 unmethylated.

3.4. SOX11 is hypermethylated in subtypes of primary endometrial tumors

To validate our finding of SOX11 hypermethylation in endometrial cancer, we analyzed methylation levels of SOX11 from TCGA endometrial cohort. Two methylation platforms from Illumina enabled us to perform comprehensive genome-wide profiling of human DNA methylation: Infinium HumanMethylation27, which includes two probes for SOX11, and HumanMethylation450, which has 24 probes. Most specimens of TCGA endometrial cohort were analyzed in HumanMethylation450 (Fig. 1b). We found that SOX11 is hypermethylated in endometrial tumors compared with adjacent normal tissue (Fig. 4a, P<0.0001). The hypermethylation phenotype was present in EEC, serous, and mixed histological endometrial primary tumors relative to normal controls (Fig. 4b, P<0.0001). As most of the specimens from TCGA endometrial cohort are from EEC tumors, we further characterized the methylation levels of SOX11 and clinical variants. Higher methylation levels of SOX11 were observed in grade 2 tumors compared with grade 1 tumors (Fig. 4c). Also, SOX11 methylation associated with MLH1 methylation and microsatellite instability (Figs. 4d–e, P<0.0001).

Fig. 4. Hypermethylation of SOX11 in TCGA endometrial cohort.

Fig. 4.

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(a) Methylation analysis of 32 paired endometrioid endometrial (EEC) tissues. (b) Dot plots demonstrating SOX11 hypermethylation in primary EEC, serous, and mixed histological endometrial tumors. (c–e) Dot plots indicating that methylation levels of SOX11 associated with tumor grade, MLH1 methylation, and MSI status. m: MLH1 methylated; u: MLH1 unmethylated.

When we analyzed the HumanMethylation27 dataset, we found that SOX11 was hypermethylated in EEC tumors compared with serous tumors (Supplementary Fig. 2a, P<0.0001), but we saw no difference among grades (Supplementary Fig. 2b). Hypermethylation of SOX11 correlated with MLH1 methylation and microsatellite instability (Supplementary Figs. 2c–d). To determine whether hypermethylation of SOX11 also correlated with SOX11 gene expression, we analyzed RNA sequence datasets from TCGA cohort, including Illumina GAII and HiSeq platforms. In both sets of data, only a small percentage of endometrial tumors expressed SOX11 mRNA (Supplementary Figs. 2e–f). In contrast, SOX4 and SOX12 (members of SOXC) were overexpressed in paired endometrial tumors, EEC, and serous tumors (Supplementary Fig. 2g), indicating that SOX11 mRNA might not be expressed in primary endometrial tumors.

3.5. Hypermethylated SOX11 is a tumor biomarker for early stage endometrial cancer but is not found in serum

As SOX11 expression is very low in most endometrial specimens (>75%), we determined whether SOX11 methylation could be a biomarker for endometrial cancer. We first examined DNA methylation of SOX11 in 12 paired early stage EEC tissues, using pyrosequencing analysis. Two paired primers (Fig. 1b) were designed within the CpG island of SOX11 (Fig. 1b). Methylation levels of SOX11 in primary tumors were higher than those in their adjacent normal specimens on each CpG site and the average of each region (P<0.001; Figs. 5a–b). We also determined whether SOX11 methylation could be detected in cell-free liquid biopsies from early stage endometrial cancer patients. Genomic DNA was isolated from serum obtained before surgery and 3 months afterwards. Pyrosequencing indicated that SOX11 was not hypermethylated in either pre-surgical or follow-up serum (Figs. 5c–d), suggesting that hypermethylated SOX11 DNA from early-stage tumors was not deposited into the circulation.

Fig. 5. Hypermethylation of SOX11 in early stage endometrial tumors.

Fig. 5.

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(a–b) DNA methylation of SOX11 CpG sites in early stage endometrial tumors and paired adjacent normal endometria as determined by pyrosequencing. (c–d) DNA methylation in serum DNA from early stage endometrial cancer patients before and after surgery as determined by pyrosequencing.

4. Discussion

The SOX family of transcription factors are essential regulators of development, tissue homeostasis, regeneration, and cell-fate reprogramming [7]. Previously, we found that SOX4 was overexpressed and played a role in endometrial cancer [4, 5]. Because the SOX family is highly conserved and could be functionally redundant, we hypothesized that other SOX family members could lose gene expression by DNA hypermethylation. The current study identified multiple hypermethylated SOX loci. Among them, SOX11 displayed unique hypermethylation in EEC, serous, and mixed histological primary tumors. Methylation of SOX11 correlated with MSI and MLH1 methylation.

Recently, SOX11 has been suggested as a diagnostic marker and oncogene because of its significant expression in mantle cell lymphoma (MCL) [8]. Expression levels of SOX11 in other cancers are inconclusive, however. SOX11 was strongly expressed in medulloblastoma [9, 10], but its RNA level was significantly lower in prostate cancer tissues than in benign prostatic hyperplasia [11]. In ovarian cancer, SOX11 mRNA expression was higher in epithelial ovarian cancers, where it associated with better disease-specific or recurrence-free survival [12, 13]. SOX11 was also overexpressed [14–16] in all subtypes of malignant breast tumors (luminal A and B, basal-like, HER+, and triple-negative). Of note, SOX11 localized in the nucleus correlated with low-grade tumor, non-lymph node metastasis, smaller size of primary tumor, and longer overall survival [14]. In contrast, SOX11 expression associated with worse outcomes in patients with lymph-node-negative breast cancer, with increased likelihood of distant metastases and decreased overall survival [15, 16]. Genetic approaches (knockdown and overexpression) in breast malignant cells demonstrated that SOX11 promotes cell growth, migration, invasion, and tumor progression [15, 16].

In 23 specimens analyzed with RT-qPCR and immunohistochemistry, SOX11 expression was higher in endometrial cancer than in adjacent tissues, and it associated with lower disease-free and overall survival [17]. Our study did not include gene expression assays, because we examined both hypermethylation and mRNA expression in the endometrial tumor specimens from TCGA’s endometrial cohort. RNA sequencing data indicated that SOX11 expression was very low in both normal endometria and tumors, and we found no difference when we compared the normal and tumor groups in the two cohorts (n=371 and 171), using the Illumina GAII and HiSeq platforms (Supplementary Figs. 2e–f). When we used the highest expression in the normal group as the cutoff, 25% of the endometrial tumors had higher expression levels of SOX11, but there was no difference in disease-free and overall survival rates (data not shown). These in silico data suggest that SOX11 mRNA expression did not correlate with patient survival in a large endometrial cancer cohort.

Aberrant DNA methylation of SOX11 has been found in cancers such as prostate, gastric, ovarian, and chronic lymphocytic leukemia [13, 18–21]. In high-grade epithelial ovarian cancer, SOX11 was a tumor suppressor that associated with improved survival [13]. In prostate cancer, SOX11 hypermethylation associated with adverse clinicopathologic characteristics, including higher PSA levels, high Gleason scores, and perineural invasion [21]. In gastric cancer, SOX11 methylation associated with Helicobacter pylori infection and related to tumor invasion, Borrmann classification, and tumor differentiation status [19, 20].

In endometrial cancer cell lines, EEC, serous primary endometrial tumors, and even in early stage endometrial tumors, we found hypermethylation of SOX11 that correlated with MLH1 methylation and microsatellite instability (MSI). Hypermethylation did not correlate with overall and disease-free survival, however. MLH1 is a DNA mismatch repair (MMR) gene that can result in MSI when it loses functions due to mutations and hypermethylation. There is no direct evidence that SOX11 regulates the expression of MLH1 or other MMR genes. However, concurrent hypermethylation of SOX11 and MLH1 might allow the two genes to independently contribute to endometrial cancer development. In endometrial cancer cells, SOX11 expression was reactivated by a DNMT inhibitor. We also wanted to determine whether upregulation of SOX11 modulates the expression of genes that SOX11 targets when endometrial cancer cells are treated with DAC and/or TSA. Our RT-qPCR revealed very limited or inconsistent changes in gene expression of DBN1, HIG2, SETMAR, and WNT4 (Supplementary Fig. 3) [22, 23]. This might be explained by the more significant expression of SOX4 and SOX12 than of SOX11 in endometrial cancer cells (Supplementary Fig. 4), because two functional domains (the N-terminal DNA-binding domain and the C-terminal transactivation domain) are respectively >80% and >60% identical in those two SOXC proteins.

SOX11 DNA methylation has been identified in fluid specimens as a biomarker for cancer prediction. In hepatitis B virus-related hepatocellular carcinoma (HCC), SOX11 was more frequently hypermethylated in serum from HCC patients than in serum from patients with chronic hepatitis B or healthy individuals [24]. In gastric cancer, greater methylation of SOX11 was found in tumor specimens than in non-cancerous tissue and healthy controls but not in whole blood [25]. However, SOX11 methylation associated with gastric cancer risk needed to be further investigated in peripheral blood leukocytes [26]. Also, SOX11 was hypermethylated in urine sediments of cancer patients and, on a 4-gene panel, it predicted bladder cancer risk with 81% sensitivity and 97% specificity [27]. We did not detect hypermethylation of SOX11 in our serum DNA, possibly due to the small size of the cohort and the early stage of its tumors. Further studies should examine SOX11 methylation levels in cell-free DNA in a larger cohort containing diverse specimens such as late-stage tumors.

Supplementary Material

1
2

Highlights.

  • Aberrant DNA methylation of SOX loci in endometrial cancer.

  • DNA demethylation reactivates SOX11.

  • SOX11 hypermethylation associates with MSI and MLH1 methylation.

  • SOX11 methylation as a tumor biomarker for endometrial cancer.

Acknowledgements

This study was supported by NIH grants U54 CA217297 and R01 CA172279 (T. Huang) and by the Women’s Health Research Program at the Medical College of Wisconsin (YW Huang).

Footnotes

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Conflicts of interest

Dr. Mutch speaks for Clovis and Astra Zeneca. All other authors declare no conflicts of interest.

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