TAp73α drives cancer metastasis via PPI-mediated derepression of the neuronal HDAC2/REST-GABBR2 axis.

Metastasis is the leading cause of death in patients with malignant melanoma, yet the molecular and transcriptional mechanisms remain elusive. This study reveals a crucial role of the p53 homolog, TAp73α, in promoting melanoma metastasis. Using multi-omics approaches combining transcriptomics, proteomics, cistromics and 3D modeling, we discovered a paradigm-shifting mechanism by which TAp73α binds directly to HDAC2, disassembles the HDAC2/REST repressor complex and aberrantly triggers activation of the neuronal receptor GABBR2 in cancer cells. TAp73α-induced derepression of GABBR2 expression leads to upregulation of EMT markers, promotes cancer cell invasiveness and proliferation, and correlates with poor survival outcomes. Our findings redefine the function of p73 in cancer pathogenesis and identify the TAp73α-HDAC2/REST-GABBR2 axis as a novel driver of melanoma progression. These insights could guide future strategies on melanoma treatment.