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Peer-reviewedCC BYFrontiers in oncology

MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer

  • Jing Jiang1
  • Tianzi You2
  • Ziyi Zhao3
  • Binlei Sheng4
  • Zhanqi Sun3
  • Xujun Li1
4 affiliations
  1. 1Department of Breast Surgery, Ningbo No. 2 Hospital, Wenzhou Medical University , , ,
  2. 2Department if Dermatology, Traditional Chinese Medicine Hospital of Ninghai County , , ,
  3. 3Health Science Center, Ningbo University , , ,
  4. 4School of Medicine, ShaoXing University , , ,
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Abstract

Background: MYH9 is upregulated in various malignancies, but its role in breast cancer chemoresistance remains unclear. We investigated whether MYH9 regulates doxorubicin (ADR) resistance via GRP78 stabilization and PERK pathway modulation.

Methods: MYH9 expression was analyzed in breast cancer tissues and cell lines by immunohistochemistry and western blot. ADR-resistant MCF-7 and MDA-MB-231 cell lines were established. MYH9 knockdown/overexpression and GRP78 overexpression were achieved by lentiviral transduction. Protein interactions, degradation assays, PERK signaling, apoptosis, and in vivo drug responses were evaluated.

Results: MYH9 was significantly upregulated in breast cancer tissues, particularly in triple-negative breast cancer (95.2%), and further elevated in ADR-resistant cells. MYH9 overexpression enhanced ADR tolerance, while knockdown sensitized resistant cells in vitro and in vivo . Mechanistically, MYH9 directly bound GRP78 (but not CALR or GRP94), inhibiting ubiquitin-mediated proteasomal degradation. MYH9 depletion reduced GRP78 levels and activated the PERK pathway (p-eIF2α, ATF4, CHOP), promoting apoptosis via Bax/Bad upregulation and Bcl-2 downregulation. ERS induction with thapsigargin enhanced ADR sensitivity, whereas 4-PBA attenuated it. GRP78 overexpression rescued ADR resistance, confirming GRP78 dependency.

Conclusion: MYH9 confers ADR resistance in breast cancer by stabilizing GRP78 and suppressing PERK-driven apoptosis, identifying the MYH9/GRP78 axis as a potential therapeutic target for overcoming chemoresistance.

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Cite

BibTeXRIS
BibTeX
@article{jiang2026myh9,
  title = {{MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer}},
  author = {Jing Jiang and Tianzi You and Ziyi Zhao and Binlei Sheng and Zhanqi Sun and Xujun Li},
  journal = {Frontiers in oncology},
  year = {2026},
  month = oct,
  doi = {10.3389/fonc.2026.1923603},
  url = {https://europepmc.org/article/PMC/PMC13672191},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer
AU  - Jing Jiang
AU  - Tianzi You
AU  - Ziyi Zhao
AU  - Binlei Sheng
AU  - Zhanqi Sun
AU  - Xujun Li
PY  - 2026
DA  - 2026/10/02
JO  - Frontiers in oncology
DO  - 10.3389/fonc.2026.1923603
UR  - https://europepmc.org/article/PMC/PMC13672191
AB  - Background: MYH9 is upregulated in various malignancies, but its role in breast cancer chemoresistance remains unclear. We investigated whether MYH9 regulates doxorubicin (ADR) resistance via GRP78 stabilization and PERK pathway modulation.  Methods: MYH9 expression was analyzed in breast cancer tissues and cell lines by immunohistochemistry and western blot. ADR-resistant MCF-7 and MDA-MB-231 cell lines were established. MYH9 knockdown/overexpression and GRP78 overexpression were achieved by lentiviral transduction. Protein interactions, degradation assays, PERK signaling, apoptosis, and in vivo drug responses were evaluated.  Results: MYH9 was significantly upregulated in breast cancer tissues, particularly in triple-negative breast cancer (95.2%), and further elevated in ADR-resistant cells. MYH9 overexpression enhanced ADR tolerance, while knockdown sensitized resistant cells in vitro and in vivo . Mechanistically, MYH9 directly bound GRP78 (but not CALR or GRP94), inhibiting ubiquitin-mediated proteasomal degradation. MYH9 depletion reduced GRP78 levels and activated the PERK pathway (p-eIF2α, ATF4, CHOP), promoting apoptosis via Bax/Bad upregulation and Bcl-2 downregulation. ERS induction with thapsigargin enhanced ADR sensitivity, whereas 4-PBA attenuated it. GRP78 overexpression rescued ADR resistance, confirming GRP78 dependency.  Conclusion: MYH9 confers ADR resistance in breast cancer by stabilizing GRP78 and suppressing PERK-driven apoptosis, identifying the MYH9/GRP78 axis as a potential therapeutic target for overcoming chemoresistance.
SN  - 2234-943X
ER  -