E2F1 and epigenetic modifiers orchestrate breast cancer progression by regulating oxygen-dependent ESRP1 expression

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Research

Background:

• Epithelial splicing regulatory protein 1 (ESRP1) is crucial for epithelial phenotypes and cancer progression.
• ESRP1 is upregulated in early tumors but downregulated in hypoxic cancer cells, promoting epithelial-mesenchymal transition (EMT).
• Mechanisms of ESRP1 upregulation in primary tumors are poorly understood.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling ESRP1 expression during breast carcinogenesis.
• To investigate how hypoxia influences ESRP1 expression and its downstream effects.

Main Methods:

• Analysis of E2F1 expression and CpG hydroxymethylation in breast carcinoma.
• Investigation of hypoxia-induced epigenetic modifications (hydroxymethylation and methylation) at the ESRP1 promoter.
• Assessment of TET3 activity and its role in regulating ESRP1 expression under hypoxia.
• Evaluation of E2F1's impact on splicing factor SRSF7 and the cancer spliceome.

Main Results:

• Elevated E2F1 and CpG hydroxymethylation of its binding motif induce ESRP1 expression in breast cancer.
• Hypoxia reduces TET3 activity, leading to loss of hydroxymethylation and gain of methylation at the E2F1 binding motif on the ESRP1 promoter.
• These epigenetic changes under hypoxia prevent E2F1 binding, diminishing ESRP1 expression.
• E2F1 upregulates SRSF7 in hypoxic cells, altering the cancer spliceome.

Conclusions:

• Spatiotemporal regulation of ESRP1 expression in breast cancer involves interplay between E2F1 and oxygen-sensitive epigenetic modifications.
• Hypoxia-induced epigenetic reprogramming silences ESRP1, contributing to EMT and potentially impacting therapeutic strategies.
• Findings reveal novel insights into ESRP1's plasticity and its role in breast cancer progression.