Xiao Xiao1, Yingying Shen2, Liyang Yin2, Jun He3, Xiaoyu Ni2, Gang Luo2, Xiguang Chen2, Wenbo Zhu2, Jing Zhong2, Jianghua Liu2, Xiuda Peng4, Xuyu Zu5. 1. Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China; Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. 2. Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. 3. Department of Spine Surgery, The Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan, China. 4. Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. Electronic address: xiudapengusc@163.com. 5. Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China. Electronic address: zuxuyu0108@hotmail.com.
Abstract
AIMS: ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. MAIN METHODS: In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α's level via targeting ER-α's expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. KEY FINDINGS: We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α's downstream genes, and promote the growth of estrogen receptor alpha (ER-α)-positive breast cancer cells. SIGNIFICANCE: Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer.
AIMS: ZBTB7A, a transcriptional repressor, accelerates the breast cancer progression. Over 70% of breast cancer samples are identified as ER-α positive. Due to the function of ZBTB7A in ER-α positive breast cancer incompletely known, we aimed to determine the role of ZBTB7A in ER-α positive cancer and explore the underlying mechanisms. MAIN METHODS: In this study, the correlation between ZBTB7A and ER-α was confirmed by tissue microarray-based and TCGA database. Then, we explore if ZBTB7A maintains ER-α's level via targeting ER-α's expression or degradation. Finally, we examined the effect of ZBTB7A on the proliferation of breast cancer cells. KEY FINDINGS: We further confirmed that ZBTB7A shows a significant positive correlation with ER-α in clinical breast cancer samples by tissue microarray-based analysis. Mechanically, we identified that the inhibition of ZBTB7A could upregulate E3 ligase TRIM25 leading to enhancement of ER-α ubiquitination and proteasomal degradation, which could partly explain the correlation between ZBTB7A and ER-α. Besides, we uncovered that ZBTB7A could also transcriptionally increase the expression of ER-α via indirectly binding to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315) in breast cancer cells. Furthermore, ZBTB7A is found to stimulate the expression of ER-α's downstream genes, and promote the growth of estrogen receptor alpha (ER-α)-positive breast cancer cells. SIGNIFICANCE: Our data revealed the novel mechanisms through which ZBTB7A manipulates ER-α level and might provide a new avenue for endocrine therapy in breast cancer.