DNp63a Silences a miRNA Program to Aberrantly Initiate aWound-Healing Program That Promotes TGFb-Induced Metastasis

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, DNp63a, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which DNp63aexpressing cells within a TGFb-rich microenvironment become positively selected formetastatic dissemination.Orthotopic transplantation of DNp63a-expressing human osteosarcoma cells into athymicmice resulted in larger andmore frequent lungmetastases than transplantation of control cells. Mechanistic investigations revealed that DNp63a repressed miR-527 and miR-665, leading to the upregulation of two TGFb effectors, SMAD4 and TbRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for DNp63a in the normal wound-healing response. We show that DNp63a-mediated repression of miR-527/665 controls a TGFb-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236–51. 2016 AACR.