Skin cutaneous melanoma (SKCM) is caused by the malignant transformation of melanocytes. It is the most aggressive form of skin cancer, associated with high mortality and rapid metastatic potential (Arnold et al., 2022). Early melanoma can be treated with surgery; however, advanced melanoma has been linked to a poor prognosis and cannot be managed through surgery. Recently, immune checkpoint blockade has shown a great prospect in treating a wide variety of cancers, including lymphoma, melanoma, and squamous non-small cell lung cancer (Alencar and Moskowitz, 2019). The treatment of melanoma has improved dramatically over the past decade. Unfortunately, due to the resistance to current therapies and recurrence of melanoma, the prognosis of melanoma remains unoptimistic (Ding et al., 2019). Therefore, it is imperative to uncover the molecular mechanisms responsible for the pathogenesis of cutaneous melanoma. This knowledge would assist in the development of preventive measures and curative treatment options.

Cuproptosis is a recently discovered form of cell death; it is distinct from other known types of cell death, such as apoptosis, ferroptosis, and necroptosis (Tsvetkov et al., 2022). Copper is a type of trace metal essential for life. Proper regulation of copper levels plays a crucial role in maintaining the function of all organisms and homeostasis. Increased copper levels have been detected in various malignancies, stimulating the proliferation, angiogenesis, and metastasis of tumor cells (Oliveri, 2022). Copper deficiency impairs the function of copper-binding enzymes, whereas copper accumulation induces cellular death (Kahlson and Dixon, 2022). As reported by Tsvetkov et al., cuproptosis dependent on mitochondrial respiration regulated by targeting lipoylated components of the tricarboxylic acid (TCA) cycle. They found seven genes (FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1 and PDHB) conferred resistance to cuproptosis, while three genes (MTF1, GLS, and CDKN2A) sensitized the cells to cuproptosis through whole-genome CRISPR-Cas9 selection screen (Tsvetkov et al., 2022). The Fe–S cluster protein FDX1 is key regulator of cuproptosis among these cuproptosis related genes (Huo et al., 2023). FDX1 was considered act as the upstream of LA pathway, and under the regulation of FDX1, LIAS linked lipoyl moiety to DLAT, which was essential for the function of mitochondria. Recent study found a significant difference in the expression of copper death-related genes between SKCM and normal tissues, suggesting an association between cuproptosis and the occurrence of SKCM. Additionally, they indicate that prognostic model constructed based on cuproptosis-related genes can effectively predict prognosis information for SKCM patients, highlighting the value of copper death-related genes in melanoma prognosis prediction (Qin et al., 2023). Zhou et al. also develop a novel risk model based on cuproptosis-related lncRNAs, which predicted prognosis and indicated immune microenvironment landscape of patients with SKCM (Zhou et al., 2022).

The hippocampal (Hippo) pathway functions as a tumor suppressor by regulating Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activity. Dysregulation of this pathway has been implicated in the development and progression of various cancer types, including cutaneous malignancies (Rognoni and Walko, 2019). It is a crucial regulator of organ size discovered through studies on Drosophila tissue growth (Tapon et al., 2002). This pathway is not necessary for normal tissue homeostasis; nevertheless, it is essential in melanoma (Andl et al., 2017). It has been shown that inactivation of the Hippo pathway promotes the growth and invasion of cutaneous melanoma (Zhang et al., 2019; Zhang et al., 2020). The Hippo pathway enforces stable growth arrest of nevus melanocytes, which represents a significant barrier to the development of melanoma. Dysregulation of the Hippo pathway enables oncogenic BRAF-expressing melanocytes to bypass nevus formation and rapidly progress into malignant melanomas (Vittoria et al., 2022). Thus, the Hippo pathway represents a promising therapeutic target in a subset of melanomas; however, the role of Hippo signaling in cuproptosis of SKCM is poorly defined.

YAP1 is recognized as the downstream oncogene of the Hippo pathway (Wu et al., 2018). Proteins involved in the Hippo pathway modulate the nuclear localization of transcription co-activators YAP and TAZ to regulate organ size. Large tumor suppressor kinase 1/2 (LATS1/2) phosphorylate serine residues (at least five in YAP) to repress YAP and TAZ, leading to their binding with 14-three to three proteins and cytoplasmic sequestration. YAP and TAZ, particularly proteins belonging to the TEA domain transcription factors (TEAD) family, modulate gene expression via transcription factors. While YAP1 is not frequently mutated in human melanoma, amplifications and mutations of YAP1 have been observed. Menzel et al. found that copy number gains directly affected YAP in 4%–10% of patients, while the copy number of known Hippo pathway-related genes was affected in 62% of patients with melanoma (Menzel et al., 2014). A significant correlation between YAP staining and reduced patient survival in primary melanoma has been discovered (Menzel et al., 2014; Shain et al., 2015; Zhang et al., 2019).

Cuproptosis, as a newly discovered form of cell death, holds significant research value in SKCM. Meanwhile, the Hippo pathway, known for its importance in various cancers, including SKCM, has unclear mutual regulation with the occurrence of cuproptosis. Therefore, in this study, we conducted a systematic investigation of the association between cuproptosis-related genes and the Hippo pathway in patients with SKCM, based on an analysis of data obtained from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. We propose that the expression of Hippo pathway genes is aberrant and positively correlated with the expression of copper death genes in SKCM. Combining the two pathway related genes, a prognostic model constructed demonstrates an effective differentiation of prognosis among SKCM patients. Regulating YAP1 can influence the expression of key genes in cuproptosis, suggesting their potential as therapeutic targets for SKCM.

In the present study, we analyzed data downloaded from the TCGA and GEO databases. The results highlight that Hippo pathway-related genes were differentially expressed between SKCM and normal tissues. We further found a positive correlation between the expression of cuproptosis-related genes and levels of Hippo pathway-related genes in SKCM. Low diagnosis rates and properties for early metastasis are the main reasons responsible for poor prognosis and high mortality. Thus, we decided to conduct a bioinformatics analysis for the identification of effective biomarkers that could assist in early detection of disease. According to the LASSO analyses, a total of 10 Hippo pathway-related genes were identified in this study. Of note, this stepwise dimensionality reduction approach for identifying key prognostic genes and constructing a risk model has been extensively documented in the literature and is a highly reliable method (Guo et al., 2022; Yang et al., 2022). Moreover, subsequent research has confirmed the superior prognostic ability of the risk model. Next, we added cuproptosis-related genes to the prognostic signatures to construct a more effective prognostic signature for melanoma. Surprisingly, the addition of cuproptosis-related genes (i.e., PDHA1, CDKN2A, SLC31A1) into new model improved its clinical usefulness in SKCM.

Targeting the Hippo/YAP/TAZ signaling pathway may provide promising opportunities for cancer therapy. Notably, this pathway acts as a tumor suppressor, and abnormal YAP/TAZ activity has been implicated in various types of skin cancer. In the past, some studies have also revealed that the Hippo pathway may be involved in the mechanisms of melanoma progression. The Hippo pathway is a highly conserved signaling cascade; it was initially identified in Drosophila melanogaster as being responsible for larval growth, and later implicated in human cancers as a major tumor suppressor pathway (Ma et al., 2019; Moya and Halder, 2019). The pathway consists of a core kinase cascade beginning with STK4, which phosphorylates and activates large tumor suppressor kinases LATS1 and LATS2 (Hansen et al., 2015; Meng et al., 2016). The Hippo pathway has been identified as a crucial tumor suppressor in melanoma, and YAP/TAZ have emerged as promising therapeutic targets for the treatment of human melanoma in numerous studies. Oncogenic BRAF expression induces activation of the Hippo pathway and cell cycle arrest in vitro through a cell-intrinsic mechanism. Hyperactive mitogen-activated protein kinase (MAPK) signaling alters the cytoskeleton, partly by decreasing RhoA signaling, which indirectly leads to Hippo pathway activation (Vittoria et al., 2022). Moreover, studies observed co-heterozygous loss of LATS1/2 and amplification of YAP1 in primary and metastatic human melanoma (Menzel et al., 2014; Zhang et al., 2019).

Copper is implicated in the pathogenesis of cancer, promoting both tumorigenesis and metastasis (Oliveri, 2022). Depending on mitochondrial respiration, copper-induced cell death represents a newly identified form of regulated cell death that is distinct from other well-characterized regulated cell death modalities, including apoptosis, ferroptosis, and necroptosis (Tsvetkov et al., 2022). Under normal circumstances, cells maintain proper levels of intracellular copper through homeostatic mechanisms. These regulatory mechanisms prevent excessive copper accumulation, thereby avoiding cellular damage. An imbalance between intracellular and extracellular copper levels can cause irreversible damage to tumor tissue (Liu et al., 2022). Recently, several in vitro experiments have demonstrated that FDX1 promotes the growth and migration of melanoma cells (Liu et al., 2022). This finding suggests that FDX1, which functions as a cuproptosis-related gene, serves as a diagnostic indicator for melanoma. Melanoma is more likely to occur in individuals who express high levels of FDX1; hence, this gene could serve as a prognostic marker for patients with melanoma. At present, some studies suggested that the Hippo pathway might have relationship with ferroptosis in cancer (Ren et al., 2022). Currently, no studies have demonstrated the regulatory role of the Hippo pathway in cuproptosis. Therefore, an innovative aspect of our research is the discovery that the Hippo pathway have a regulatory effect on cuproptosis.

Owing to its potential for early metastasis, melanoma is the most fatal type of skin cancer (Nikolaou and Stratigos, 2014). The interaction between genetic susceptibility and environmental exposure gives rise to multiple risk factors (Rastrelli et al., 2014). The surgical treatment of early melanoma is effective; however, advanced melanoma has a dismal prognosis, rendering surgery an unsuitable option for many patients. For these patients, a treatment plan involving immunotherapy, radiotherapy, chemotherapy, or a combination of these therapies may be considered (Altonsy et al., 2020; Wang et al., 2021). The treatment of malignant melanoma has significantly improved with the advent of targeted therapies and immune checkpoint blockade agents. Nevertheless, the challenge of primary and acquired resistance to treatment persists (Sosman et al., 2012; Postow et al., 2015). Therefore, constructing a prognostic model capable of distinguishing SKCM based on a large sample size dataset has significant clinical value. TCGA and GEO, among other large-scale public databases, provide transcriptome profiles for numerous types of cancer. Use of the GEO database, which contains expression profile data of a wide range of cancers, has enabled scientists to rapidly identify genes closely associated with cancer (Song et al., 2020). In recent years, the application of machine learning to life sciences has become increasingly common. Numerous studies have demonstrated that machine learning plays a crucial role in mining new information from medical big data (Hong et al., 2020; Nayarisseri et al., 2021; Panja et al., 2021). The use of machine learning assists in predicting the occurrence and prognosis of cancer; moreover, this approach can lead to the discovery of new biomarkers of cancer (Chen et al., 2022). Therefore, an extensive body of research has investigated the prognosis and metastasis of melanoma. Thus far, research focused on predicting the prognosis of patients with melanoma based on the expression levels of pyroptotic genes and the tumor microenvironment status (Huang et al., 2020; Wang et al., 2020; Ju et al., 2021). It may be possible to better understand the molecular mechanism underlying the progression of SKCM by identifying the signaling pathways that differ between risk stratification groups. In this study, we also constructed two prognostic models that can effectively differentiate between melanoma patients with favorable and unfavorable prognoses, providing assistance for clinical diagnosis and treatment.

Immunotherapy is a crucial treatment modality for melanoma. The difference in immune cell infiltration is a key factor in determining the effectiveness of immunotherapy. By analyzing the degree of immune cell infiltration in different YAP1 expression subgroups, we identified significant differences in various cells such as Treg cells and M2 macrophages between the two groups. Treg cells, characterized by the expression of fork head box P3 (FOXP3), play a crucial role in maintaining self-tolerance by suppressing immune responses to both self- and non-self antigens in an antigen-nonspecific manner (Fontenot et al., 2005; Overacre-Delgoffe et al., 2017). The lack of Treg cells can result in evident autoimmune disease. However, tumor-infiltrating Treg cells are associated with poor clinical outcomes. It has been shown that they promote cancer progression due to their ability to inhibit antitumor immunity (Facciabene et al., 2012). Therefore, they pose a major obstacle to the success of immunotherapy (Arce Vargas et al., 2017). The depletion of tumor-infiltrating Treg cells exerted synergistic effects with an immune checkpoint inhibitor for tumor eradication (Van Damme et al., 2021). The metabolic pathways of M1 and M2 macrophages exhibit distinct characteristics. Over the past few years, extensive studies have demonstrated that macrophages exhibit a complete tricarboxylic acid cycle, which provides electron transport chain substrate (Viola et al., 2019). Tumor-associated macrophages are exposed to low oxygen and glucose concentrations and AMP-activated protein kinase (AMPK) activation, thereby promoting their anti-inflammatory properties (McGettrick and O'Neill, 2020). A negative correlation was found between YAP1 expression and Treg cell infiltration. However, a positive correlation was found between YAP1 expression and M2 macrophage infiltration. Hence, upregulation of YAP1 might enhance the response to immunotherapy by inhibiting Treg cell infiltration into the tumor microenvironment.

In conclusion, we found that eight Hippo pathway-related genes were downregulated in melanoma, exhibiting prognostic value. Furthermore, YAP1 was positively correlated with M2 macrophages and negatively correlated with Treg cell infiltration. There was a significant positive correlation between cuproptosis-related genes and Hippo pathway-related genes in SKCM. The ability to predict the prognosis of patients with SKCM could be improved following the addition of Hippo pathway-related genes into the novel risk model based on cuproptosis-related genes. Moreover, downregulation of YAP1 could lead to lower expression of FDX1. The presence of this factor may serve as a prognostic indicator for patients with melanoma undergoing immunotherapy.