Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma

Abstract Background Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase II (TOP2) po...

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Autores principales:	Qiancheng Shi, Ning Liu, Lei Yang, Yi Chen, Yanwen Lu, Hongqian Guo, Xiaodong Han, Dongmei Li, Weidong Gan
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Renal cell carcinoma Xp11.2 Estradiol Estrogen receptor Topoisomerase TFE3 Medicine R Cytology QH573-671
Acceso en línea:	https://doaj.org/article/fa875bb1b1e1498695558cc830fa6c45
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spelling	oai:doaj.org-article:fa875bb1b1e1498695558cc830fa6c452021-11-21T12:13:33ZEstradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma10.1186/s12964-021-00790-31478-811Xhttps://doaj.org/article/fa875bb1b1e1498695558cc830fa6c452021-11-01T00:00:00Zhttps://doi.org/10.1186/s12964-021-00790-3https://doaj.org/toc/1478-811XAbstract Background Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase II (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2. Methods Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes. Results Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to TFE3 translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides, TFE3 was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of TFE3 breaks. Conclusion Our results indicate that E2 amplifies TOP2β-mediated TFE3 breaks by ERα-dependent pathway, and E2 upregulates TFE3 by NRF1 to increase the risk of TFE3 breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis. Video AbstractQiancheng ShiNing LiuLei YangYi ChenYanwen LuHongqian GuoXiaodong HanDongmei LiWeidong GanBMCarticleRenal cell carcinomaXp11.2EstradiolEstrogen receptorTopoisomeraseTFE3MedicineRCytologyQH573-671ENCell Communication and Signaling, Vol 19, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Renal cell carcinoma Xp11.2 Estradiol Estrogen receptor Topoisomerase TFE3 Medicine R Cytology QH573-671
spellingShingle	Renal cell carcinoma Xp11.2 Estradiol Estrogen receptor Topoisomerase TFE3 Medicine R Cytology QH573-671 Qiancheng Shi Ning Liu Lei Yang Yi Chen Yanwen Lu Hongqian Guo Xiaodong Han Dongmei Li Weidong Gan Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
description	Abstract Background Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase II (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2. Methods Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes. Results Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to TFE3 translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides, TFE3 was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of TFE3 breaks. Conclusion Our results indicate that E2 amplifies TOP2β-mediated TFE3 breaks by ERα-dependent pathway, and E2 upregulates TFE3 by NRF1 to increase the risk of TFE3 breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis. Video Abstract
format	article
author	Qiancheng Shi Ning Liu Lei Yang Yi Chen Yanwen Lu Hongqian Guo Xiaodong Han Dongmei Li Weidong Gan
author_facet	Qiancheng Shi Ning Liu Lei Yang Yi Chen Yanwen Lu Hongqian Guo Xiaodong Han Dongmei Li Weidong Gan
author_sort	Qiancheng Shi
title	Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
title_short	Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
title_full	Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
title_fullStr	Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
title_full_unstemmed	Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
title_sort	estradiol increases risk of topoisomerase iiβ-mediated dna strand breaks to initiate xp11.2 translocation renal cell carcinoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/fa875bb1b1e1498695558cc830fa6c45
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Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma

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