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FBXO24 Suppresses Breast Cancer Tumorigenesis by Targeting LSD1 for Ubiquitination
Bo Dong1,2, Xiang Song1,2,3,4, Xinzhao Wang1,2
1Department of Pharmacology & Nutritional Sciences, University of Kentucky School of Medicine, Lexington, Kentucky.
Abstract:
Lysine-specific demethylase 1 (LSD1), a critical chromatin modulator, functions as an oncogene by demethylation of H3K4me1/2. The stability of LSD1 is governed by a complex and intricate process involving ubiquitination and deubiquitination. Several deubiquitinases preserve LSD1 protein levels. However, the precise mechanism underlying the degradation of LSD1, which could mitigate its oncogenic function, remains unknown. To gain a better understanding of LSD1 degradation, we conducted an unbiased siRNA screening targeting all the human SCF family E3 ligases. Our screening identified FBXO24 as a genuine E3 ligase that ubiquitinates and degrades LSD1. As a result, FBXO24 inhibits LSD1-induced tumorigenesis and functions as a tumor suppressor in breast cancer cells. Moreover, FBXO24 exhibits an inverse correlation with LSD1 and is associated with a favorable prognosis in breast cancer patient samples. Taken together, our study uncovers the significant role of FBXO24 in impeding breast tumor progression by targeting LSD1 for degradation.
Implications:
Our study provides comprehensive characterization of the significant role of FBXO24 in impeding breast tumor progression by targeting LSD1 for degradation.
Insights
FBXO24 targets the oncogene Lysine-specific demethylase 1 (LSD1) for degradation, inhibiting breast tumor progression. This discovery identifies FBXO24 as a tumor suppressor, offering new therapeutic strategies for breast cancer.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Mechanisms of Oncogenesis
- Tumor Suppressor Functions
Background:
- Lysine-specific demethylase 1 (LSD1) is a chromatin modifier that acts as an oncogene in various cancers.
- LSD1 stability is regulated by ubiquitination and deubiquitination, but its degradation pathway remains unclear.
- Understanding LSD1 degradation is crucial for developing strategies to mitigate its oncogenic function.
Purpose of the Study:
- To identify the E3 ligase responsible for LSD1 degradation.
- To elucidate the role of FBXO24 in regulating LSD1 stability and function.
- To investigate the potential of FBXO24 as a tumor suppressor in breast cancer.
Main Methods:
- Unbiased siRNA screening of human SCF family E3 ligases.
- Ubiquitination assays to confirm FBXO24's ligase activity towards LSD1.
- Analysis of FBXO24 and LSD1 expression in breast cancer patient samples.
Main Results:
- FBXO24 was identified as the E3 ligase that ubiquitinates and degrades LSD1.
- FBXO24 suppresses LSD1-induced tumorigenesis and acts as a tumor suppressor in breast cancer cells.
- FBXO24 expression inversely correlates with LSD1 levels and predicts favorable prognosis in breast cancer patients.
Conclusions:
- FBXO24 targets LSD1 for degradation, thereby inhibiting breast tumor progression.
- FBXO24 functions as a critical tumor suppressor by controlling LSD1 stability.
- Targeting the FBXO24-LSD1 axis presents a potential therapeutic strategy for breast cancer.
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