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Background <p>Histone deacetylase inhibitors (HDACi) are clinically approved drugs for the treatment of hematological malignancies synergizing with chemotherapy. However, despite the long history of HDACi, the mechanistic underpinnings of this synergism have remained unclear.</p> Methods <p>Using transmission electron microscopy, we identified autophagy and ER-stress in HDACi-treated cells. We quantified ER-phagy and ER-stress with reporter systems by using 3D-deconvolution microscopy and flow cytometry. We complemented these data with qPCR and Western blot results. Apoptosis rates were assessed using a caspase assay and flow cytometry, and large public datasets were utilized.</p> Results <p>HDAC blockade results in specific upregulation of the selective autophagy receptor FAM134B (RETREG1) and the induction of ER-phagy. Combined with the chemotherapeutic drug Gemcitabine, this results in subsequent elevated ER-stress levels and apoptosis. Inhibiting the distinct ER-stress branches fully rescues this process. Broadening the scope of these findings, certain non-HDAC-inhibitory and clinically approved compounds like Loperamide and Nelfinavir are able to induce FAM134B and could hence constitute novel Gemcitabine-synergizing molecules. Additionally, pancreatic cancer patients with high <i>FAM134B</i> expression have significantly longer survival rates under chemotherapy.</p> Conclusion <p>In summary, we provide mechanistic evidence for ER-phagy playing a hitherto unknown central role in the clinical synergy between HDACi and chemotherapy.</p>

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ER-phagy mediates the anti-tumoral synergism between HDAC inhibition and chemotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月26日

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  • Felix J. Gössl,
  • Pierfrancesco Polo,
  • Frederik Helmprobst,
  • André Menzenbach,
  • Alexander Visekruna,
  • Thomas M. Gress,
  • Till Adhikary,
  • Matthias Lauth

摘要

Background

Histone deacetylase inhibitors (HDACi) are clinically approved drugs for the treatment of hematological malignancies synergizing with chemotherapy. However, despite the long history of HDACi, the mechanistic underpinnings of this synergism have remained unclear.

Methods

Using transmission electron microscopy, we identified autophagy and ER-stress in HDACi-treated cells. We quantified ER-phagy and ER-stress with reporter systems by using 3D-deconvolution microscopy and flow cytometry. We complemented these data with qPCR and Western blot results. Apoptosis rates were assessed using a caspase assay and flow cytometry, and large public datasets were utilized.

Results

HDAC blockade results in specific upregulation of the selective autophagy receptor FAM134B (RETREG1) and the induction of ER-phagy. Combined with the chemotherapeutic drug Gemcitabine, this results in subsequent elevated ER-stress levels and apoptosis. Inhibiting the distinct ER-stress branches fully rescues this process. Broadening the scope of these findings, certain non-HDAC-inhibitory and clinically approved compounds like Loperamide and Nelfinavir are able to induce FAM134B and could hence constitute novel Gemcitabine-synergizing molecules. Additionally, pancreatic cancer patients with high FAM134B expression have significantly longer survival rates under chemotherapy.

Conclusion

In summary, we provide mechanistic evidence for ER-phagy playing a hitherto unknown central role in the clinical synergy between HDACi and chemotherapy.