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Nuclear ErbB2 represses DEPTOR transcription to inhibit autophagy in breast cancer cells

Yanli Bi1,2,3, Longyuan Gong1,2,3, Pengyuan Liu3

  • 1Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Cell Death & Disease
|April 15, 2021
PubMed

Insights

Nuclear ErbB2, a receptor tyrosine kinase, represses DEPTOR transcription, inhibiting autophagy. This novel nuclear function of ErbB2 activates mTORC1, impacting breast cancer cell signaling and autophagy regulation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • ErbB2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase often overexpressed in breast cancer.
  • While ErbB2's role in extracellular signaling is known, its nuclear functions are poorly understood.
  • DEPTOR is a direct inhibitor of the mechanistic target of rapamycin (mTOR) pathway.

Purpose of the Study:

  • To investigate the novel functions of nuclear ErbB2 in breast cancer cells.
  • To elucidate the mechanism by which nuclear ErbB2 regulates DEPTOR transcription.
  • To understand the impact of nuclear ErbB2 on autophagy and the PI3K/AKT/mTOR pathway.

Main Methods:

  • Chromatin immunoprecipitation assays to identify nuclear ErbB2 binding sites.
  • Reporter assays to assess transcriptional regulation of DEPTOR.
  • Kinase activity assays and nuclear translocation studies.
  • Analysis of autophagy induction and mTORC1 activity.

Main Results:

  • Nuclear ErbB2 directly binds to the DEPTOR promoter, repressing its transcription.
  • ErbB2 kinase activity is essential for its nuclear localization and DEPTOR repression.
  • Repressed DEPTOR by nuclear ErbB2 leads to mTORC1 activation and inhibition of autophagy.
  • This mechanism involves the PI3K/AKT/mTOR pathway.

Conclusions:

  • Nuclear ErbB2 acts as a transcriptional repressor of DEPTOR.
  • This nuclear function of ErbB2 provides a novel mechanism for autophagy regulation.
  • Targeting nuclear ErbB2 activity could offer new therapeutic strategies for breast cancer.

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