Mechanism of LINC00958 in ferroptosis of breast cancer through the SRSF1/GPX4 axis

TL;DR

This study shows how LINC00958 promotes breast cancer cell survival by preventing a type of cell death called ferroptosis through interactions with SRSF1 and GPX4.

Contribution

The study reveals a novel mechanism involving LINC00958, SRSF1, and GPX4 in regulating ferroptosis in breast cancer.

Findings

LINC00958 downregulation inhibits breast cancer cell proliferation and promotes ferroptosis.

LINC00958 binds to SRSF1, enhancing GPX4 mRNA stability and expression.

GPX4 overexpression counteracts the effects of LINC00958 downregulation on ferroptosis.

Abstract

Breast cancer (BC) is the most common cancer among women. Ferroptosis is a novel iron-dependent form of cell death and affects cancer development. This study was conducted to explore the role of long intergenic non-protein coding RNA958 (LINC00958) in the ferroptosis of BC cells.

The expression levels of LINC00958 and glutathione peroxidase 4 (GPX4) in BC cell lines were first determined. After the interference of LINC00958, cell proliferation was assessed by cell counting kit-8 and colony formation assays, and ferroptosis was tested by measurements of ferric ion content, reactive oxygen species (ROS), glutathione (GSH), and acyl-CoA synthetase long-chain family member 4 (ACSL4). The binding of serine/arginine splicing factor 1 (SRSF1) to LINC00958/GPX4 was analyzed by RNA immunoprecipitation. GPX4 mRNA stability was determined after actinomycin D treatment. Rescue experiments were conducted to test the role of GPX4 in ferroptosis. Finally, mouse transplantation tumors were designed to verify the role of LINC00958.

LINC00958 was highly-expressed in BC cells. LINC00958 downregulation inhibited proliferation and promoted ferroptosis, while LINC00958 overexpression promoted proliferation and inhibited ferroptosis. LINC00958 directly bound to SRSF1, increased the occupancy of SRSF1 on GPX4 mRNA, and augmented the mRNA stability of GPX4. GPX4 overexpression neutralized the promotive role of LINC00958 downregulation in ferroptosis of BC cells.

Binding of LINC00958 to SRSF1 increases the occupancy of SRSF1 on GPX4 mRNA and the mRNA stability and expression of GPX4, thereby inhibiting ferroptosis of BC cells.

The online version contains supplementary material available at 10.1186/s41065-025-00469-6.

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