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Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Chianese, Ugo ; Papulino, Chiara ; Passaro, Eugenia ; Evers, Tom MJ ; Babaei, Mehrad ; Toraldo, Antonella ; De Marchi, Tommaso LU ; Niméus, Emma LU ; Carafa, Vincenzo and Nicoletti, Maria Maddalena , et al. (2022) In Molecular Metabolism 64.
Abstract

Objective: 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. Methods: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to... (More)

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AR, Cell stiffness, KDMs, Lipid, Metabolism, PCa
in
Molecular Metabolism
volume
64
article number
101561
publisher
Elsevier
external identifiers
  • scopus:85136069603
  • pmid:35944897
ISSN
2212-8778
DOI
10.1016/j.molmet.2022.101561
language
English
LU publication?
yes
id
2eb5247a-7873-4838-be91-b2b03b6c2a30
date added to LUP
2022-11-22 14:57:10
date last changed
2024-04-15 20:36:47
@article{2eb5247a-7873-4838-be91-b2b03b6c2a30,
  abstract     = {{<p>Objective: 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. Methods: 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. Results: 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. Conclusions: 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.</p>}},
  author       = {{Chianese, Ugo and Papulino, Chiara and Passaro, Eugenia and Evers, Tom MJ and Babaei, Mehrad and Toraldo, Antonella and De Marchi, Tommaso and Niméus, Emma and Carafa, Vincenzo and Nicoletti, Maria Maddalena and Del Gaudio, Nunzio and Iaccarino, Nunzia and Randazzo, Antonio and Rotili, Dante and Mai, Antonello and Cappabianca, Salvatore and Mashaghi, Alireza and Ciardiello, Fortunato and Altucci, Lucia and Benedetti, Rosaria}},
  issn         = {{2212-8778}},
  keywords     = {{AR; Cell stiffness; KDMs; Lipid; Metabolism; PCa}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Molecular Metabolism}},
  title        = {{Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics}},
  url          = {{http://dx.doi.org/10.1016/j.molmet.2022.101561}},
  doi          = {{10.1016/j.molmet.2022.101561}},
  volume       = {{64}},
  year         = {{2022}},
}