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<p>Cholesterol biosynthesis is more activated in triple negative breast cancer (TNBC) than in other subtype breast cancer and plays essential role in facilitating TNBC. However, the regulatory network and how cholesterol biosynthesis contribute to TNBC development and progression are not well elucidated. Here, we found that reticulum membrane protein complex 2 (EMC2) is highly expressed in TNBC and predicts short survival of patients. In vitro and in vivo experiments displayed that EMC2 could promote TNBC growth. We also displayed that EMC2 could increase intracellular cholesterol biosynthesis by regulating Farnesyltransferase 1 (FDFT1) expression. Mechanistically, we validated that EMC2 interacted with heat shock protein 90(HSP90) to sustain FDFT1 protein quality and correctly located in the ER membrane through protecting it from endoplasmic reticulum associated degradation (ERAD). Furthermore, EMC2 decreased TNBC cell ferroptosis susceptibility through elevating intracellular cholesterol contents. Collectively, our findings shed a new insight that EMC2 is critical for boosting cholesterol biosynthesis and ferroptosis resistance. Targeting EMC2 could be a promising novel therapeutic target for TNBC treatment.</p>

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EMC2 promotes triple negative breast cancer growth by protecting FDFT1 from endoplasmic reticulum associated degradation to impair ferroptosis susceptibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月10日

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  • Xinrui Dong,
  • Huijuan Dai,
  • Linli Yao,
  • Yanping Lin,
  • Yaohui Wang,
  • Ye Li,
  • Xueli Zhang,
  • Liheng Zhou,
  • Jinsong Lu,
  • Wenjin Yin

摘要

Cholesterol biosynthesis is more activated in triple negative breast cancer (TNBC) than in other subtype breast cancer and plays essential role in facilitating TNBC. However, the regulatory network and how cholesterol biosynthesis contribute to TNBC development and progression are not well elucidated. Here, we found that reticulum membrane protein complex 2 (EMC2) is highly expressed in TNBC and predicts short survival of patients. In vitro and in vivo experiments displayed that EMC2 could promote TNBC growth. We also displayed that EMC2 could increase intracellular cholesterol biosynthesis by regulating Farnesyltransferase 1 (FDFT1) expression. Mechanistically, we validated that EMC2 interacted with heat shock protein 90(HSP90) to sustain FDFT1 protein quality and correctly located in the ER membrane through protecting it from endoplasmic reticulum associated degradation (ERAD). Furthermore, EMC2 decreased TNBC cell ferroptosis susceptibility through elevating intracellular cholesterol contents. Collectively, our findings shed a new insight that EMC2 is critical for boosting cholesterol biosynthesis and ferroptosis resistance. Targeting EMC2 could be a promising novel therapeutic target for TNBC treatment.