Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch.
Animals
Biomarkers
CD8-Positive T-Lymphocytes
/ immunology
Cell Line, Tumor
Cell Nucleus
/ genetics
Cellular Reprogramming
/ drug effects
Female
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Histone Demethylases
/ genetics
Humans
Immunotherapy
Mice
Neoplasms
/ etiology
T-Box Domain Proteins
/ genetics
T-Lymphocytes
/ drug effects
Treatment Outcome
EOMES
LSD1
PD-1
T cell exhaustion
cancer
circulating tumor cells
immunotherapy resistance
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
22
02
2020
accepted:
15
05
2020
entrez:
3
7
2020
pubmed:
3
7
2020
medline:
13
4
2021
Statut:
epublish
Résumé
Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1
Identifiants
pubmed: 32612611
doi: 10.3389/fimmu.2020.01228
pmc: PMC7309504
doi:
Substances chimiques
Biomarkers
0
EOMES protein, human
0
T-Box Domain Proteins
0
Histone Demethylases
EC 1.14.11.-
KDM1A protein, human
EC 1.5.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1228Informations de copyright
Copyright © 2020 Tu, McCuaig, Tan, Hardy, Seddiki, Ali, Dahlstrom, Bean, Dunn, Forwood, Tsimbalyuk, Smith, Yip, Malik, Prasanna, Milburn and Rao.
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