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<p>Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC.</p> Graphical Abstract <p></p>

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CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Jianghua Li,
  • Lu Xu,
  • Jiayu Wang,
  • Xuning Wang,
  • Yuting Lin,
  • Alex Yutian Zou,
  • Fangli Ren,
  • Yinyin Wang,
  • Jun Li,
  • Zhijie Chang

摘要

Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC.

Graphical Abstract