Abstract
| Original language | English |
|---|---|
| Article number | 1351 |
| Pages (from-to) | 1-17 |
| Number of pages | 17 |
| Journal | Frontiers in Immunology |
| Volume | 10 |
| Issue number | JUN |
| DOIs | |
| Publication status | Published - 2019 |
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Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer. / Tan, Abel H. Y.; Tu, Wenjuan; Mccuaig, Robert; Hardy, Kristine; Donovan, Thomasina; Tsimbalyuk, Sofiya; Forwood, Jade K.; Rao, Sudha.
In: Frontiers in Immunology, Vol. 10, No. JUN, 1351, 2019, p. 1-17.Research output: Contribution to journal › Article
TY - JOUR
T1 - Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer
AU - Tan, Abel H. Y.
AU - Tu, Wenjuan
AU - Mccuaig, Robert
AU - Hardy, Kristine
AU - Donovan, Thomasina
AU - Tsimbalyuk, Sofiya
AU - Forwood, Jade K.
AU - Rao, Sudha
PY - 2019
Y1 - 2019
N2 - Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
AB - Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
KW - macrophage polarization
KW - LSD1
KW - CoREST
KW - breast cancer
KW - epigenetics
KW - tumor microenvironment
KW - tumor associated macrophages
KW - Tumor associated macrophages
KW - Macrophage polarization
KW - Tumor microenvironment
KW - Epigenetics
KW - Breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85068986089&partnerID=8YFLogxK
UR - http://www.mendeley.com/research/lysinespecific-histone-demethylase-1a-regulates-macrophage-polarization-checkpoint-molecules-tumor-m
U2 - 10.3389/fimmu.2019.01351
DO - 10.3389/fimmu.2019.01351
M3 - Article
VL - 10
SP - 1
EP - 17
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - JUN
M1 - 1351
ER -