Melanoma represents one of the most aggressi e forms of skin cancer with an increasing occurrence worldwide, often characterized b resistance to standard therapies, finall causing patient death. For these reasons, there is an urgent need to find no el druggable targets to impro e melanoma treatment strategies. We ha e pre iousl demonstrated that the anti-apoptotic members of the Bcl-2 famil proteins, such as Bcl-2, Bcl-xL and Bcl-2L10 can enhance disease aggressi eness and progression through their non-canonical functions, promoting the de elopment of a tumor microen ironment that fa ors metastasis formation, angiogenesis, tumor stage ad ancement and resistance to therapies. Here, our aim was to delineate a transcriptional signature and no el cellular pathwa s uniquel modulated b Bcl-2 respect to Bcl-xL in human melanoma cells. To this end, we performed RN seq anal sis after siRN-mediated transient knockdown of Bcl-2 or Bcl-xL. Subsequentl, we conducted a gene ontolog anal sis to un eil a distinct Bcl-2 transcriptional fingerprint, finding in ol ement in the modulation of different genes belonging to the Hippo pathwa. Further alidation was carried out through qRT-PCR assa s to confirm the expression of genes influenced b Bcl-2 and associated with the Hippo pathwa. dditionall, Western blotting anal sis was emplo ed to stud the protein expression of upstream regulators of P in relation with ar ing le els of Bcl-2 protein. The impact of P silencing in Bcl-2 o erexpressing melanoma cells was functionall assessed through migration assa s, demonstrating that P can be one of the mediators of Bcl-2 functions. In conclusion, our findings …