Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells.

in Science advances by Giulia Marotta, Daniela Osti, Elena Zaccheroni, Brunella Costanza, Stefania Faletti, Adriana Marinaro, Cristina Richichi, Deborah Mesa, Simona Rodighiero, Chiara Soriani, Enrica Migliaccio, Federica Ruscitto, Chiara Priami, Sara Sigismund, Francesco Manetti, Dario Polli, Galina V Beznusenko, Mara-Camelia Rusu, Francesco Favero, Davide Corà, Domenico A Silvestris, Angela Gallo, Valentina Gambino, Fabio Alfieri, Sara Gandini, Matthias J Schmitt, Gaetano Gargiulo, Roberta Noberini, Tiziana Bonaldi, Giuliana Pelicci

TLDR

  • LSD1i selectively targets TICs by impairing their oxidative metabolism and generating reactive oxygen species, making it a potential therapeutic strategy for glioblastoma.
  • The study found that disruptions in ER and mitochondrial balance are key factors in determining the efficacy of LSD1-targeted therapy.

Abstract

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.

Overview

  • The study investigates the therapeutic potential of LSD1 inhibition in glioblastoma using DDP_38003 (LSD1i) and its effects on tumor-initiating cells (TICs).
  • The researchers found that LSD1i acts as an endoplasmic reticulum (ER) stressor, activating the integrated stress response and altering mitochondrial structure and function.
  • The study aimed to understand the mechanisms of resistance to LSD1i and discovered that postglycosylphosphatidylinositol attachment to proteins inositol deacylase 1 (PGAP1) is a mediator of resistance to LSD1i.

Comparative Analysis & Findings

  • LSD1i selectively targets TICs by hampering their adaptability to stress, impairing their oxidative metabolism, and generating reactive oxygen species.
  • TICs with enhanced glycolysis benefit from LSD1-directed therapy, while metabolically silent TICs maintain ER and mitochondrial homeostasis, adapting to stress conditions.
  • Disruptions in ER and mitochondrial balance hold promise for improving LSD1-targeted therapy efficacy and overcoming treatment resistance.

Implications and Future Directions

  • The study highlights the significance of ER and mitochondrial balance in determining the efficacy of LSD1-targeted therapy.
  • Future studies should investigate ways to improve the treatment efficacy of LSD1i by targeting ER and mitochondrial balance and overcoming resistance mechanisms.
  • Additionally, the study suggests that identifying PGAP1 as a mediator of resistance to LSD1i can lead to the development of new therapeutic strategies to overcome treatment resistance.
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