HuR enhances FSTL1 transcript stability to promote invasion and metastasis of squamous cell carcinoma

Squamous cell carcinoma (SCC) is a lethal malignancy with a high propensity for metastasis. Follistatin-like 1 (FSTL1), a pro-metastatic glycoprotein, is absent from healthy epithelia and aberrantly upregulated in SCC. The FSTL1 transcript encodes two alternative gene products whose dominance is post-transcriptionally regulated via a bistable switch. In healthy epithelia, FSTL1 mRNA is destabilized by binding of KH-type splicing regulatory protein (KSRP), and processed as a primary microRNA encoding miR-198. In SCC, KSRP downregulation terminates miR-198 processing, enabling FSTL1 translation. Here, we identify HuR (Human Antigen R) as an upstream regulator of FSTL1 and describe how downregulation of KSRP is permissive, but not sufficient, to promote sustained FSTL1 expression. Moreover, we demonstrate how the interplay between two RNA-binding proteins controls the translation of pro-oncogenic FSTL1. Increased expression of HuR in SCC outcompetes KSRP and enhances FSTL1 transcript stability, enabling persistent FSTL1 expression and activation of downstream metastatic pathways.