The Knockdown of <i>ETV4</i> Inhibits the Papillary Thyroid Cancer Development by Promoting Ferroptosis Upon <i>SLC7A11</i> Downregulation

Abstract

Papillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancies. Herein, we aimed to provide a new viewpoint for the PTC progression and explore a new target for the effective therapy for PTC. We found that E26 transformation specific (ETS) variant 4 (<i>ETV4</i>, an ETS family transcription factor) was upregulated in PTC tissues and cells. <i>In vitro</i> experiments exhibited that silencing <i>ETV4</i> suppressed PTC cell proliferation and cell cycle progression, while the overexpression of <i>ETV4</i> gained the opposite results. Dual-luciferase reporter assay highlighted that <i>ETV4</i> could upregulate the solute carrier family 7 member 11 (<i>SLC7A11</i>, a key role for cysteine uptake in ferroptosis) transcription by binding to its promoter region directly. Moreover, the viability inhibition of PTC cells induced by the knockdown of <i>ETV4</i> was at least partly through the promotion of ferroptosis upon the downregulation of <i>SLC7A11</i>. In <i>in vivo</i> experiment, the results showed that the downregulation of <i>ETV4</i> repressed the tumor development through the low expression of <i>SLC7A11</i>, and the <i>ETV4</i> overexpression obtained the contrary effects. Overall, the data suggested that the knockdown of <i>ETV4</i> suppressed the PTC progression by promoting ferroptosis upon <i>SLC7A11</i> downregulation.