Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer
Abstract Background The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous. Methods In this study, we compared high-grade se...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-021-08276-8 |
| _version_ | 1818439488110592000 |
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| author | Yichao Li Sushil K. Jaiswal Rupleen Kaur Dana Alsaadi Xiaoyu Liang Frank Drews Julie A. DeLoia Thomas Krivak Hanna M. Petrykowska Valer Gotea Lonnie Welch Laura Elnitski |
| author_facet | Yichao Li Sushil K. Jaiswal Rupleen Kaur Dana Alsaadi Xiaoyu Liang Frank Drews Julie A. DeLoia Thomas Krivak Hanna M. Petrykowska Valer Gotea Lonnie Welch Laura Elnitski |
| author_sort | Yichao Li |
| collection | DOAJ |
| description | Abstract Background The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous. Methods In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs. Results In a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs. Conclusions These data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes. |
| first_indexed | 2024-12-14T17:57:15Z |
| format | Article |
| id | doaj.art-4c559146e9d843bcbcba7858da50d4e6 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-14T17:57:15Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-4c559146e9d843bcbcba7858da50d4e62022-12-21T22:52:32ZengBMCBMC Cancer1471-24072021-07-0121111810.1186/s12885-021-08276-8Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancerYichao Li0Sushil K. Jaiswal1Rupleen Kaur2Dana Alsaadi3Xiaoyu Liang4Frank Drews5Julie A. DeLoia6Thomas Krivak7Hanna M. Petrykowska8Valer Gotea9Lonnie Welch10Laura Elnitski11School of Electrical Engineering and Computer Science, Ohio UniversityTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthSchool of Electrical Engineering and Computer Science, Ohio UniversitySchool of Electrical Engineering and Computer Science, Ohio UniversityPresent address: Dignity Health Global EducationDepartment of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh Medical SchoolTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthSchool of Electrical Engineering and Computer Science, Ohio UniversityTranslational Functional Genomics Branch, National Human Genome Research Institute, National Institutes of HealthAbstract Background The heterogeneous subtypes and stages of epithelial ovarian cancer (EOC) differ in their biological features, invasiveness, and response to chemotherapy, but the transcriptional regulators causing their differences remain nebulous. Methods In this study, we compared high-grade serous ovarian cancers (HGSOCs) to low malignant potential or serous borderline tumors (SBTs). Our aim was to discover new regulatory factors causing distinct biological properties of HGSOCs and SBTs. Results In a discovery dataset, we identified 11 differentially expressed genes (DEGs) between SBTs and HGSOCs. Their expression correctly classified 95% of 267 validation samples. Two of the DEGs, TMEM30B and TSPAN1, were significantly associated with worse overall survival in patients with HGSOC. We also identified 17 DEGs that distinguished stage II vs. III HGSOC. In these two DEG promoter sets, we identified significant enrichment of predicted transcription factor binding sites, including those of RARA, FOXF1, BHLHE41, and PITX1. Using published ChIP-seq data acquired from multiple non-ovarian cell types, we showed additional regulatory factors, including AP2-gamma/TFAP2C, FOXA1, and BHLHE40, bound at the majority of DEG promoters. Several of the factors are known to cooperate with and predict the presence of nuclear hormone receptor estrogen receptor alpha (ER-alpha). We experimentally confirmed ER-alpha and PITX1 presence at the DEGs by performing ChIP-seq analysis using the ovarian cancer cell line PEO4. Finally, RNA-seq analysis identified recurrent gene fusion events in our EOC tumor set. Some of these fusions were significantly associated with survival in HGSOC patients; however, the fusion genes are not regulated by the transcription factors identified for the DEGs. Conclusions These data implicate an estrogen-responsive regulatory network in the differential gene expression between ovarian cancer subtypes and stages, which includes PITX1. Importantly, the transcription factors associated with our DEG promoters are known to form the MegaTrans complex in breast cancer. This is the first study to implicate the MegaTrans complex in contributing to the distinct biological trajectories of malignant and indolent ovarian cancer subtypes.https://doi.org/10.1186/s12885-021-08276-8High-grade serous ovarian cancerHGSOCSerous borderline tumorSBTPITX1Estrogen receptor-alpha |
| spellingShingle | Yichao Li Sushil K. Jaiswal Rupleen Kaur Dana Alsaadi Xiaoyu Liang Frank Drews Julie A. DeLoia Thomas Krivak Hanna M. Petrykowska Valer Gotea Lonnie Welch Laura Elnitski Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer BMC Cancer High-grade serous ovarian cancer HGSOC Serous borderline tumor SBT PITX1 Estrogen receptor-alpha |
| title | Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer |
| title_full | Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer |
| title_fullStr | Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer |
| title_full_unstemmed | Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer |
| title_short | Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer |
| title_sort | differential gene expression identifies a transcriptional regulatory network involving er alpha and pitx1 in invasive epithelial ovarian cancer |
| topic | High-grade serous ovarian cancer HGSOC Serous borderline tumor SBT PITX1 Estrogen receptor-alpha |
| url | https://doi.org/10.1186/s12885-021-08276-8 |
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