Selenium-binding protein 1 suppresses tumor invasion by destabilizing MMP2 mRNA through a p21-dependent AUF1-ARE regulatory axis.

Selenium-binding protein 1 (SELENBP1) is frequently downregulated across multiple human solid tumors and has long been recognized as a tumor suppressor. Our previous work established that SELENBP1 restrained cell-cycle progression by transcriptionally inducing p21 (CDKN1A) through a p53-independent pathway, yet the molecular basis of its anti-invasive function remained unclear. Here, using bladder and colon cancer cell models with stable SELENBP1 overexpression, we show that SELENBP1 markedly inhibits cellular invasion without affecting migration, accompanied by a selective downregulation of matrix metalloproteinase 2 (MMP2). Mechanistic analyses revealed that SELENBP1 destabilizes MMP2 mRNA via its 3'-untranslated region (3'-UTR). Further, SELENBP1 upregulates the AU-rich element (ARE)-binding protein AUF1, which in turn accelerates MMP2 mRNA decay in an ARE-dependent manner. Silencing AUF1 abolished SELENBP1-mediated repression of MMP2 and restored invasive capacity, demonstrating that AUF1 is a critical mediator in this process. Importantly, we also identified p21 as an indispensable upstream regulator: SELENBP1 induced AUF1 and repressed MMP2 only in the presence of functional p21, whereas p21-deficient cells failed to transmit this regulatory cascade. Together, our findings delineate a previously unrecognized SELENBP1-p21-AUF1-MMP2 axis that links SELENBP1-mediated invasion suppression to post-transcriptional control of extracellular matrix remodeling. This study highlights SELENBP1 as a multifunctional tumor suppressor and suggests that restoring this pathway may offer therapeutic opportunities in invasive cancers.