ERK3 as a BRAF-Regulated Tumor Suppressor is a New Potential Cancer Target in Melanoma

Melanoma is the highest mortality rate skin cancer and the sixth most common cancer in the U.S..[1, 2] Arising from melanocytes, melanoma is known for frequent mutation of BRAF to its constitutive activation state BRAFV600E, thus over-activating its downstream MAPK targets ERK1/2 and contributing to melanoma progression.[3, 4, 5] ERK3, a less studied MAPK family protein which contributes to promoting lung, breast, cervical, head and neck (HNC) cancer metastasis, has also shown a correlation with upregulation of BRAF.[6, 7, 8, 9] However, the BRAF-ERK3 regulatory mechanism and the function of ERK3 in melanoma are still unclear. Here, we first elucidate the general regulation pattern that BRAFV600E and BRAF are able to upregulate ERK3 through two mechanisms: kinase activity-independent protein stabilization and kinase activity-dependent transcriptional regulation. These two mechanisms are not impacted by BRAFV600E mutation status, in concordance with our clinical result of BRAFV600E mutation decreasing in frequency with melanoma progression. We next proved that unlike in lung cancer and HNC, ERK3 functions as a melanoma tumor suppressor which inhibited both metastasis as well as tumor formation in vitro. Our microarray and immunofluorescence results suggest that ERK3 functions differently in melanoma possibly due to tissue-specific transcriptional and localization differences of ERK3. Meanwhile, microarray elucidates a group of genes clinically relevant to melanoma tumor progression is tightly correlated with ERK3 downregulation, which is found in later stage melanoma.[10] Clinical patient survival data also supports that ERK3 is a tumor suppressor in melanoma rather than an oncogene as it is in lung cancer.[11, 12] Thus, based on these preliminary data we hypothesize that melanoma may evade the usual regulation of ERK3 by BRAF, thus preventing ERK3 suppression metastasis in melanoma. We also revealed several possibilities of how melanoma escapes BRAF-ERK3 regulation from our preliminary data. Further elucidation of the mechanisms by which ERK3 is downregulated in melanoma and to restore these pathways would be a new potential target for treatment of melanoma