Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers
Abstract Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis—a process linked to drug resist...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07900-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331941230247936 |
|---|---|
| author | Baris Sergi Neslihan Yuksel-Catal Selahattin Can Ozcan Hamzah Syed Umamaheswar Duvvuri Kirill Kiselyov Ceyda Acilan |
| author_facet | Baris Sergi Neslihan Yuksel-Catal Selahattin Can Ozcan Hamzah Syed Umamaheswar Duvvuri Kirill Kiselyov Ceyda Acilan |
| author_sort | Baris Sergi |
| collection | DOAJ |
| description | Abstract Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis—a process linked to drug resistance. However, the epigenetic regulation of lysosomal exocytosis is poorly understood. We hypothesize that epigenetic modifier drugs (epidrugs) inhibiting this exocytosis could serve as potential cancer therapeutics. To explore this, we screened more than 150 epidrugs targeting various epigenetic proteins for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and lysosomal biogenesis. Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. RNA-seq analysis revealed differentially expressed genes involved in vesicular trafficking and lysosome dynamics, suggesting novel regulatory mechanisms. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates. |
| format | Article |
| id | doaj-art-10d07c2cdd0040dd9ffaa6e2c36f7039 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-10d07c2cdd0040dd9ffaa6e2c36f70392025-08-20T03:46:21ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111610.1038/s41419-025-07900-wEpidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancersBaris Sergi0Neslihan Yuksel-Catal1Selahattin Can Ozcan2Hamzah Syed3Umamaheswar Duvvuri4Kirill Kiselyov5Ceyda Acilan6Graduate School of Health Sciences, Koc UniversityGraduate School of Health Sciences, Koc UniversityResearch Center for Translational Medicine (KUTTAM), Koc UniversityResearch Center for Translational Medicine (KUTTAM), Koc UniversityNYU Grossman School of Medicine, NYU Langone HealthDepartment of Biological Sciences, University of PittsburghResearch Center for Translational Medicine (KUTTAM), Koc UniversityAbstract Epigenetic changes drive gene expression alterations, contributing to oncogenesis and drug resistance. Lysosomes play a key role in cell signaling and sequestering toxins, including chemotherapeutic agents, which are then expelled through lysosomal exocytosis—a process linked to drug resistance. However, the epigenetic regulation of lysosomal exocytosis is poorly understood. We hypothesize that epigenetic modifier drugs (epidrugs) inhibiting this exocytosis could serve as potential cancer therapeutics. To explore this, we screened more than 150 epidrugs targeting various epigenetic proteins for their combined cytotoxic effects with cisplatin, their impact on lysosomal exocytosis, and lysosomal biogenesis. Two type I PRMT inhibitors, MS023 and GSK3368715, showed synergy with cisplatin, reduced cell viability, and inhibited lysosomal exocytosis without altering lysosomal biogenesis gene expression. RNA-seq analysis revealed differentially expressed genes involved in vesicular trafficking and lysosome dynamics, suggesting novel regulatory mechanisms. These inhibitors also synergized with other lysosome-sequestered drugs, indicating a broader application in overcoming drug resistance. Analysis of patient data further linked lower type I PRMT levels to better responses, highlighting their potential as combination therapy candidates to enhance chemotherapy efficacy and improve cancer survival rates.https://doi.org/10.1038/s41419-025-07900-w |
| spellingShingle | Baris Sergi Neslihan Yuksel-Catal Selahattin Can Ozcan Hamzah Syed Umamaheswar Duvvuri Kirill Kiselyov Ceyda Acilan Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers Cell Death and Disease |
| title | Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| title_full | Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| title_fullStr | Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| title_full_unstemmed | Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| title_short | Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| title_sort | epidrug screening identifies type i prmt inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers |
| url | https://doi.org/10.1038/s41419-025-07900-w |
| work_keys_str_mv | AT barissergi epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT neslihanyukselcatal epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT selahattincanozcan epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT hamzahsyed epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT umamaheswarduvvuri epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT kirillkiselyov epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers AT ceydaacilan epidrugscreeningidentifiestypeiprmtinhibitorsasmodulatorsoflysosomalexocytosisanddrugsensitivityincancers |