Gössl Felix J, Polo Pierfrancesco, Helmprobst Frederik, Menzenbach André, Visekruna Alexander, Gress Thomas M, Adhikary Till, Lauth Matthias
Clinic of Gastroenterology, Endocrinology and Metabolism, Center for Tumor- and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, Marburg, 35043, Germany.
Core Facility for Mouse Pathology and Electron Microscopy, Philipps University Marburg, Marburg, 35043, Germany.
Cell Commun Signal. 2025 Apr 26;23(1):202. doi: 10.1186/s12964-025-02198-9.
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.
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.
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.
In summary, we provide mechanistic evidence for ER-phagy playing a hitherto unknown central role in the clinical synergy between HDACi and chemotherapy.
组蛋白去乙酰化酶抑制剂（HDACi）是临床上已获批用于治疗血液系统恶性肿瘤的药物，可与化疗协同作用。然而，尽管HDACi应用历史悠久，但这种协同作用的机制基础仍不清楚。
我们使用透射电子显微镜在HDACi处理的细胞中鉴定出自噬和内质网应激。我们通过三维去卷积显微镜和流式细胞术，利用报告系统对内质网自噬和内质网应激进行定量分析。我们用定量聚合酶链反应（qPCR）和蛋白质免疫印迹（Western blot）结果补充这些数据。使用半胱天冬酶检测法和流式细胞术评估细胞凋亡率，并利用大型公共数据集。
HDAC阻断导致选择性自噬受体FAM134B（RETREG1）特异性上调，并诱导内质网自噬。与化疗药物吉西他滨联合使用时，这会导致随后内质网应激水平升高和细胞凋亡。抑制不同的内质网应激分支可完全挽救这一过程。拓展这些发现的范围，某些非HDAC抑制性且临床上已获批的化合物，如洛哌丁胺和奈非那韦，能够诱导FAM134B表达，因此可能构成新型的与吉西他滨协同的分子。此外，FAM134B表达高的胰腺癌患者在化疗下的生存率显著更长。
总之，我们提供了内质网自噬在HDACi与化疗的临床协同作用中发挥迄今未知的核心作用的机制证据。
