Melanoma is the deadliest skin cancer with a very poor prognosis in advanced stages. Although targeted and immune therapies have improved survival, not all patients benefit from these treatments. The mitogen-activated protein kinase ERK5 supports the growth of melanoma cells in vitro and in vivo. However, ERK5 inhibition results in cell-cycle arrest rather than appreciable apoptosis. To clarify the role of ERK5 in melanoma growth, we performed transcriptomic analyses following ERK5 knockdown in melanoma cells expressing BRAFV600E and found that cellular senescence was among the most affected processes. In melanoma cells expressing either wild-type or mutant (V600E) BRAF, both genetic and pharmacologic inhibition of ERK5 elicited cellular senescence, as observed by a marked increase in senescence-associated β-galactosidase activity and p21 expression. In addition, depletion of ERK5 from melanoma cells resulted in increased levels of CXCL1, CXCL8, and CCL20, proteins typically involved in the senescence-associated secretory phenotype. Knockdown of p21 suppressed the induction of cellular senescence by ERK5 blockade, pointing to p21 as a key mediator of this process. In vivo, ERK5 knockdown or inhibition with XMD8–92 in melanoma xenografts promoted cellular senescence. Based on these results, small-molecule compounds targeting ERK5 constitute a rational series of prosenescence drugs that may be exploited for melanoma treatment. Significance: This study shows that targeting ERK5 induces p21-mediated cellular senescence in melanoma, identifying a prosenescence effect of ERK5 inhibitors that may be exploited for melanoma treatment.

Dual-specificity protein phosphatases (DUSPs) are a family of proteins that dephosphorylate both phospho-serine/threonine and phospho-tyrosine residues of Mitogen-Activated Protein Kinases (MAPKs). MAPKs are involved in a large number of cellular processes, including proliferation, differentiation, apoptosis, and stress responses. Therefore, dysregulation or improper functioning of the MAPK signalling is involved in the onset and progression of several diseases, including cancer. Likewise, dysregulation of DUSPs markedly affects cancer biology. The importance of MAPKs in the modulation of tumour development has been known for a long time, and MAPKs are consistently used as molecular targets for cancer therapy. However, in the last decade, DUSPs have acquired a greater interest as possible therapeutic targets to regulate MAPK activity and to prevent resistance mechanisms to MAPK-targeting therapies. Moreover, the possibility of exploiting DUSPs as biomarkers for the diagnosis and prognosis of specific types of cancer is also emerging. In this review, we report what is known in the literature on the role of DUSPs in cancer onset and progression, focusing on those targeting the extracellular signal-regulated kinases (ERKs), in particular ERK1/2 and ERK5 conventional MAPKs. The specific role of each ERK-targeting DUSP in supporting or hampering cancer progression in the context of different types of cancer is also discussed.

Dual-specificity protein phosphatases (DUSPs) are a family of proteins that dephosphorylate both phospho-serine/threonine and phospho-tyrosine residues of Mitogen-Activated Protein Kinases (MAPKs). MAPKs are involved in a large number of cellular processes, including pro-liferation, differentiation, apoptosis and stress response. Therefore, dysregulation, or improper functioning of the MAPK signalling is involved in the onset and progression of several diseas-es, including cancer. Likewise, dysregulation of DUSPs markedly affects cancer biology. The importance of MAPKs in the modulation of tumour development has been known for a long time, and MAPKs are consistently used as molecular targets for cancer therapy. However, in the last decade, DUSPs have acquired a greater interest as possible therapeutic targets to regulate MAPK activity, and to prevent resistance mechanisms to MAPK-targeting therapies. Moreover, the possibility of exploiting DUSPs as biomarkers for the diagnosis and prognosis of specific types of cancer is also emerging. In this review, we report what is known in the literature on the role of DUSPs in cancer onset and progression, focusing on those active on the extracellular signal-regulated kinases (ERK), in particular on ERK1/2 and ERK5 conventional MAPKs. The specific role of each ERK-targeting DUSP in supporting or hampering cancer progression in the context of different types of cancer is also discussed.