2. Academic Validation
  3. Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways

Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways

  • EMBO J. 2024 Dec;43(24):6336-6363. doi: 10.1038/s44318-024-00290-3.
Xianping Wang # 1 2,  Yifan Guo # 3 4,  Peng Lin # 3 4,  Min Yu 5,  Sha Song 3 4,  Wenyan Xu 3 4,  Du Kong 3 4,  Yin Wang 3 4 6,  Yanxiao Zhang 3 4,  Fei Lu 7,  Qi Xie 8 9,  Xianjue Ma 10 11
Affiliations

Affiliations

  • 1 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China. wangxianping@westlake.edu.cn.
  • 2 School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China. wangxianping@westlake.edu.cn.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China.
  • 4 School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China.
  • 5 Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 6 Department of Diabetes & Cancer Metabolism, Beckman Research Institute of City of Hope National Medical Center, Duarte, CA, 91010, USA.
  • 7 State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 8 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China. xieqi@westlake.edu.cn.
  • 9 School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China. xieqi@westlake.edu.cn.
  • 10 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, Zhejiang, China. maxianjue@westlake.edu.cn.
  • 11 School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China. maxianjue@westlake.edu.cn.
  • # Contributed equally.
PMID: 39516282 DOI: 10.1038/s44318-024-00290-3
Abstract

Hormone therapy resistance and the ensuing aggressive tumor progression present a significant clinical challenge. However, the mechanisms underlying the induction of tumor malignancy upon inhibition of steroid hormone signaling remain poorly understood. Here, we demonstrate that Drosophila malignant epithelial tumors show a similar reduction in ecdysone signaling, the main steroid hormone pathway. Our analysis of ecdysone-induced downstream targets reveals that overexpression of the nuclear receptor E75, particularly facilitates the malignant transformation of benign tumors. Genome-wide DNA binding profiles and biochemistry data reveal that E75 not only binds to the transcription factors of both Hippo and Notch pathways, but also exhibits widespread co-binding to their target genes, thus contributing to tumor malignancy. We further validated these findings by demonstrating that depletion of NR1D2, the mammalian homolog of E75, inhibits the activation of Hippo and Notch target genes, impeding glioblastoma progression. Together, our study unveils a novel mechanism by which hormone inhibition promotes tumor malignancy, and describes an evolutionarily conserved role of the oncogene E75/NR1D2 in integration of Hippo and Notch pathway activity during tumor progression.

Keywords

Glioblastoma; Hippo Signaling; NR1D2; Notch Signaling; Steroid Hormone.

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