ERK3 is transcriptionally upregulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in non-melanoma skin cancers

Abstract

Background p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. ∆Np63α is the main isoform of p63 and highly expressed in Non-melanoma skin cancer (NMSC). Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose biochemical features and cellular regulation are distinct from those of conventional MAPKs such as ERK1/2. While ERK3 has been shown to be upregulated in lung cancers and head and neck cancers, in which it promotes cancer cell migration and invasion, little is known about the implication of ERK3 in NMSCs. Methods Fluorescent immunohistochemistry was performed to evaluate the expression levels of ΔNp63α and ERK3 in normal and NMSC specimens. Dunnett’s test was performed to compare mean fluorescence intensity (MFI, indicator of expression levels) of p63 or ERK3 between normal cutaneous samples and NMSC samples. A mixed effects (ANOVA) test was used to determine the correlation between ΔNp63α and ERK3 expression levels (MFI). The regulation of ERK3 by ΔNp63α was studied by qRT-PCR, Western blot and luciferase assay. The effect of ERK3 regulation by ΔNp63α on cell migration was measured by performing trans-well migration assay. Results The expression level of ∆Np63α is upregulated in NMSCs compared to normal tissue. ERK3 level is significantly upregulated in AK and SCC in comparison to normal tissue and there is a strong positive correlation between ∆Np63α and ERK3 expression in normal skin and skin specimens of patients with AK, SCC or BCC. Further, we found that ∆Np63α positively regulates ERK3 transcript and protein levels in A431 and HaCaT skin cells, underlying the upregulation of ERK3 expression and its positive correlation with ∆Np63α in NMSCs. Moreover, similar to the effect of ∆Np63α depletion, silencing ERK3 greatly enhanced A431 cell migration. Restoration of ERK3 expression under the condition of silencing ∆Np63α counteracted the increase in cell migration induced by the depletion of ∆Np63α. Mechanistically, ERK3 inhibits the phosphorylation of Rac1 G-protein and the formation of filopodia of A431 skin SCC cells. Conclusions ERK3 is positively regulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in NMSC.

ERK3/MAPK6 dictates Cdc42/Rac1 activity and ARP2/3-dependent actin polymerization

“…We have recently demonstrated that ERK3 directly contributed to AP-1/c-Jun activation, IL-8 production and chemotaxis 52 . Emerging studies have further shown that ERK3 functions in a context- and tissue-specific manner in controlling tumourigenesis and metastasis 50, 51, 53, 56, 81, 88, 89 . Mice expressing a catalytically inactive ERK3 mutant survive to adulthood and are fertile, but the kinase activity of ERK3 is necessary for optimal postnatal growth.…”

Pharmacoinformatics-based investigation of bioactive compounds of Rasam (South Indian recipe) against human cancer

“…MAPK6 is shown to be a key factor for organogenesis, cancer cell growth and invasiveness. MAPK6 overexpression has been detected in numerous human cancers, including squamous cell lung carcinoma, oral squamous cell carcinoma, gastric cancer, breast cancer and melanoma 53 . DNA microarray studies have produced inconsistent information about the regulation of MAPK6 expression in cancer.…”

“In medio stat virtus”: Insights into hybrid E/M phenotype attitudes

“…ΔNp63α is the predominant and physiologically significant isoform of p63 in epithelial tissues (Alshammari et al, 2021). Recently, ΔNp63α has been proposed as another possible PSF since it can induce a pEMT by activating Slug (SNAIL2) as well as inhibiting ZEB via miR-205 (Dang et al, 2016).…”