ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis
Abhipsa Sinha1, Krishan Kumar Saini1,2, Aakash Chandramouli3
1Division of Cancer Biology, Council of Scientific & Industrial Research-Central Drug Research Institute, Lucknow 226031, India.
Abstract:
Triple-negative breast cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed to the absence of progesterone receptor. Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyperacetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis, and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.
Insights
Targeting acyl-CoA synthetase 4 (ACSL4) can reduce triple-negative breast cancer (TNBC) metastasis. This metabolic enzyme drives TNBC spread by altering gene expression and epigenetic marks, offering a new therapeutic target.
Area of Science:
- Oncology
- Metabolic Research
- Epigenetics
Background:
- Triple-negative breast cancer (TNBC) presents a significant unmet medical need due to its aggressive metastasis and limited targeted therapies.
- Lipid metabolism, particularly fatty acid oxidation (FAO), is increasingly recognized as a key driver of cancer cell metastasis.
- Acyl-CoA synthetase 4 (ACSL4) is identified as a critical regulator in metabolic reprogramming within cancer.
Purpose of the Study:
- To investigate the role of acyl-CoA synthetase 4 (ACSL4) in the metastasis of triple-negative breast cancer (TNBC).
- To elucidate the molecular mechanisms by which ACSL4 influences TNBC cell migration, invasion, and metastatic spread.
- To explore the potential of targeting ACSL4 as a therapeutic strategy for TNBC.
Main Methods:
- Analysis of FAO regulatory gene expression in breast cancer tissues.
- Genetic ablation and pharmacological inhibition of ACSL4 in TNBC models.
- Global transcriptome analysis to assess gene expression changes.
- Assessment of histone acetylation marks (H3K9ac, H3K27ac) and SNAIL expression.
- Correlation analysis of ACSL4, epigenetic marks, and SNAIL in human TNBC metastasis.
Main Results:
- ACSL4 is selectively overexpressed in TNBC, correlating with the absence of progesterone receptor.
- Loss of ACSL4 function significantly impairs TNBC metastatic potential.
- ACSL4 promotes TNBC migration and invasion by modulating FAO and acetyl-CoA levels.
- ACSL4-driven hyperacetylation of H3K9ac and H3K27ac leads to SNAIL overexpression, facilitating metastasis.
- A positive correlation exists between ACSL4, H3K9ac, H3K27ac, and SNAIL in human TNBC metastasis.
Conclusions:
- ACSL4 plays a critical role in orchestrating TNBC metastasis through a mechanism involving metabolic reprogramming and epigenetic modifications.
- Targeting ACSL4 presents a promising therapeutic avenue for combating TNBC metastasis.
- Understanding the interplay between metabolism and epigenetics in TNBC provides a rational basis for developing novel anti-metastatic therapies.
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