Journal article
Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer
Cancer letters, Vol.600, 217182
09/28/2024
DOI: 10.1016/j.canlet.2024.217182
PMCID: PMC11384719
PMID: 39154703
Abstract
Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.
•LSD1 plays a critical role in TNBC pathogenesis.•LSD1-mediated histone demethylation is a vital epigenetic mechanism leading to TFPI2 suppression in TNBC.•Restoration of TFPI2 is required for the antitumor effect of LSD1 inhibition.•Targeting LSD1 rewires the local immune environment, reinvigorates exhausted T cells, and reinforces the antitumor immune response by regulating TFPI2.•LSD1 ablation-mediated TFPI2 induction is critical for the in vitro and in vivo potentiating effects of paclitaxel chemotherapy and anti-PD-1 immunotherapy.
Details
- Title: Subtitle
- Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer
- Creators
- Tiezheng Gu - UPMC Hillman Cancer CenterShauna N. Vasilatos - UPMC Hillman Cancer CenterJun Yin - UPMC Hillman Cancer CenterYe Qin - University of PittsburghLin Zhang - UPMC Hillman Cancer CenterNancy E. Davidson - Fred Hutch Cancer CenterYi Huang - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer letters, Vol.600, 217182
- DOI
- 10.1016/j.canlet.2024.217182
- PMID
- 39154703
- PMCID
- PMC11384719
- NLM abbreviation
- Cancer Lett
- ISSN
- 0304-3835
- eISSN
- 1872-7980
- Publisher
- Elsevier B.V
- Grant note
- NIH: CA260357, CA236271, P30 CA086862
This work was supported by NIH grants CA260357 (to YH) , CA236271 (to LZ) , P30 CA086862 (University of Iowa Holden Comprehensive Cancer Center) and the Breast Cancer Research Foundation (to NED) .
- Language
- English
- Date published
- 09/28/2024
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984699523402771
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