In this paper, using two independent cancer cell models, we unveiled a novel regulatory mechanism where inhibition of miR-17-5p and/or miR-106-5p leads to recover TRIM8-mediated p53 tumour suppressor activity and strong inhibition of N-MYC-dependent cell proliferation by p53-dependent N-MYC destabilization through miR-34a up-regulation. Here, TP53 is linked to cancer.