Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer

Abel H. Y. Tan, Wenjuan Tu, Robert Mccuaig, Kristine Hardy, Thomasina Donovan, Sofiya Tsimbalyuk, Jade K. Forwood, Sudha Rao

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.
Original languageEnglish
Article number1351
Pages (from-to)1-17
Number of pages17
JournalFrontiers in Immunology
Volume10
Issue numberJUN
DOIs
Publication statusPublished - 2019

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Histone Demethylases
Triple Negative Breast Neoplasms
Tumor Microenvironment
Phenelzine
Flavin-Adenine Dinucleotide
Macrophages
Switch Genes
Co-Repressor Proteins
Zinc Fingers
Phenotype
Neoplasms
Proteins

Cite this

Tan, Abel H. Y. ; Tu, Wenjuan ; Mccuaig, Robert ; Hardy, Kristine ; Donovan, Thomasina ; Tsimbalyuk, Sofiya ; Forwood, Jade K. ; Rao, Sudha. / Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer. In: Frontiers in Immunology. 2019 ; Vol. 10, No. JUN. pp. 1-17.
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title = "Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer",
abstract = "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.",
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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 journalArticle

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

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SP - 1

EP - 17

JO - Frontiers in Immunology

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SN - 1664-3224

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