Details

Autor(en) / Beteiligte

• Chianese, Ugo
• Papulino, Chiara
• Passaro, Eugenia
• Evers, Tom MJ
• Babaei, Mehrad
• Toraldo, Antonella
• De Marchi, Tommaso
• Niméus, Emma
• Carafa, Vincenzo
• Nicoletti, Maria Maddalena
• Del Gaudio, Nunzio
• Iaccarino, Nunzia
• Randazzo, Antonio
• Rotili, Dante
• Mai, Antonello
• Cappabianca, Salvatore
• Mashaghi, Alireza
• Ciardiello, Fortunato
• Altucci, Lucia
• Benedetti, Rosaria

Titel

Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Ist Teil von

• Molecular metabolism (Germany), 2022-10, Vol.64, p.101561-101561, Article 101561

Ort / Verlag

Elsevier GmbH

Erscheinungsjahr

2022

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program. We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells. Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC. •KDMs inhibition promotes increases H3K4me2 and H3K27me3 in PCa and CRPC, which causes cancer selective pro-apoptotic pathways.•KDMs regulate AR expression in PCa and CRPC, reducing ATP production, mitochondrial respiration and intermediate metabolites availability.•Epigenetic controls metabolic pathways and redirects lipid metabolic cascade.•KDMs inhibition alters lipid distribution and composition, impacting on physical and mechanical properties of PCa and CRPC.