Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells
Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in various biological processes, including metabolic pathways. We demonstrated the therapeutic potential of its pharmacological inhibition in glioblastoma using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Through biological, metabolic, and omic approaches, we now show that LSD1i acts as an endoplasmic reticulum (ER) stressor, activating the integrated stress response and altering mitochondrial structure and function. These effects impair TICs' oxidative metabolism and generate reactive oxygen species, further amplifying cellular stress. LSD1i also impairs TICs' glycolytic activity, causing their metabolic decline. TICs with enhanced glycolysis benefit from LSD1-directed therapy. Conversely, metabolically silent TICs mantain ER and mitochondrial homeostasis, adapting to stress conditions, including LSD1i treatment. A dropout short hairpin RNA screening identifies postglycosylphosphatidylinositol attachment to proteins inositol deacylase 1 (PGAP1) as a mediator of resistance to LSD1i. Disruptions in ER and mitochondrial balance holds promise for improving LSD1-targeted therapy efficacy and overcoming treatment resistance.
Authors
- Valentina Gambino (ORCID: https://orcid.org/0000-0002-8265-8281)
- Domenico Alessandro Silvestris (ORCID: https://orcid.org/0000-0003-1861-1750)
- Federica Ruscitto (ORCID: https://orcid.org/0000-0003-2717-9306)
- Francesco Manetti (ORCID: https://orcid.org/0000-0002-8223-0074)
- Elena Zaccheroni (ORCID: https://orcid.org/0000-0002-0161-9804)
- Brunella Costanza (ORCID: https://orcid.org/0000-0001-8279-805X)
- Sara Gandini (ORCID: https://orcid.org/0000-0002-1348-4548)
- Chiara Priami (ORCID: https://orcid.org/0000-0001-8041-2432)
- Daniela Osti (ORCID: https://orcid.org/0000-0001-7794-3400)
- Matthias Jürgen Schmitt (ORCID: https://orcid.org/0000-0001-8296-5858)
- Fabio Alfieri (ORCID: https://orcid.org/0000-0001-7173-0105)
- Dario Polli (ORCID: https://orcid.org/0000-0002-6960-5708)
- Francesco Favero (ORCID: https://orcid.org/0000-0003-3482-8335)
- Chiara Soriani (ORCID: https://orcid.org/0000-0003-4363-6597)
- Angela Gallo (ORCID: https://orcid.org/0000-0003-0297-1807)
- Tiziana Bonaldi (ORCID: https://orcid.org/0000-0003-3556-1265)
- Simona Rodighiero (ORCID: https://orcid.org/0000-0003-4236-7823)
- Davide Corà (ORCID: https://orcid.org/0000-0003-4123-1705)
- Sara Sigismund (ORCID: https://orcid.org/0000-0002-1396-4453)
- Roberta Noberini (ORCID: https://orcid.org/0000-0002-7267-1079)
- G Marotta (ORCID: https://orcid.org/0000-0002-9750-3709)
- Mara-Camelia Rusu (ORCID: https://orcid.org/0000-0002-8369-3580)
- Cristina Richichi (ORCID: https://orcid.org/0000-0002-3184-0358)
- Stefania Faletti (ORCID: https://orcid.org/0000-0003-2489-1795)
- Gaetano Gargiulo (ORCID: https://orcid.org/0000-0001-5414-4251)
- Enrica Migliaccio (ORCID: https://orcid.org/0000-0002-3989-8773)
- Giuliana Pelicci (ORCID: https://orcid.org/0000-0003-0986-8255)
- Galina Beznusenko
- D. Mesa (ORCID: https://orcid.org/0009-0003-0290-1136)
- Adriana Marinaro (ORCID: https://orcid.org/0009-0008-1897-0474)
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Milan (IT)
- Max Delbrück Center (DE)
- IFOM (IT)
- Human Technopole (IT)
- Bambino Gesù Children's Hospital (IT)
- Center for Biomolecular Nanotechnologies (IT)
- European Institute of Oncology (IT)
- Politecnico di Milano (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1126/sciadv.adt2724
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.81