2. Academic Validation
  3. SMURF1 facilitates estrogen receptor ɑ signaling in breast cancer cells

SMURF1 facilitates estrogen receptor ɑ signaling in breast cancer cells

  • J Exp Clin Cancer Res. 2018 Feb 12;37(1):24. doi: 10.1186/s13046-018-0672-z.
Huijie Yang 1,  Na Yu 2,  Juntao Xu 3 4,  Xiaosheng Ding 5,  Wei Deng 6,  Guojin Wu 7,  Xin Li 1,  Yingxiang Hou 1,  Zhenhua Liu 1,  Yan Zhao 1,  Min Xue 1,  Sifan Yu 8,  Beibei Wang 1,  Xiumin Li 2 9,  Gang Niu 10 11,  Hui Wang 12 13,  Jian Zhu 14 15,  Ting Zhuang 16 17
Affiliations

Affiliations

  • 1 Henan Key Laboratory of immunology and targeted therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan Province, People's Republic of China.
  • 2 Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
  • 3 Phil Rivers Technology (Beijing) Ltd, Beijing, China.
  • 4 Department of Cancer genomics, LemonData biotech (Shenzhen) Ltd, Shenzhen, China.
  • 5 Department of Medical Oncology, Peking University International Hospital, Beijing, China.
  • 6 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center of Digestive Diseases, Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center of Digestive Diseases, Beijing, 100050, China.
  • 7 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 8 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Renal cancer and Melanoma, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
  • 9 Center for Cancer Research, Xinxiang Medical University, Xinxiang, Henan, China.
  • 10 Phil Rivers Technology (Beijing) Ltd, Beijing, China. g.niu@lemondata.com.cn.
  • 11 Department of Cancer genomics, LemonData biotech (Shenzhen) Ltd, Shenzhen, China. g.niu@lemondata.com.cn.
  • 12 Henan Key Laboratory of immunology and targeted therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan Province, People's Republic of China. wanghui@xxmu.edu.cn.
  • 13 Xinxiang Medical University, School of Laboratory Medicine, Xinxiang, Henan Province, China. wanghui@xxmu.edu.cn.
  • 14 Henan Key Laboratory of immunology and targeted therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan Province, People's Republic of China. jian.zhu@utsouthwestern.edu.
  • 15 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. jian.zhu@utsouthwestern.edu.
  • 16 Henan Key Laboratory of immunology and targeted therapy, School of Laboratory Medicine, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, 453003, Henan Province, People's Republic of China. 77090993@qq.com.
  • 17 Xinxiang Medical University, School of Laboratory Medicine, Xinxiang, Henan Province, China. 77090993@qq.com.
PMID: 29433542 DOI: 10.1186/s13046-018-0672-z
Abstract

Background: Estrogen Receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent Cancer progression. ER alpha positive breast Cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast Cancer therapy.

Methods: SMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by Real-Time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha.

Results: Here, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48-specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment.

Conclusions: Our study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast Cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast Cancer treatment.

Keywords

Breast cancer; ER alpha; Protein stability; SMURF1; Ubiquitination.

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