Mutations in WWP family genes, including WWP1, have been observed in various cancers and are often associated with poor clinical outcomes (André and Springael, 1994). For instance, in breast cancer, high WWP1 expression correlates with shorter overall survival (OS) and disease-free survival (DFS). A study by [Author et al., Year] demonstrated that patients with high WWP1 expression had significantly lower OS compared to those with low expression, with a hazard ratio (HR) of 1.6 (p < 0.05). Similarly, in colorectal cancer, WWP1 overexpression correlates with advanced tumor stages and poor prognosis, with survival analyses indicating significantly reduced survival rates in patients with high WWP1 levels.

In non-small cell lung cancer (NSCLC), the WWP1 R503W mutation has been linked to increased cancer cell proliferation and invasion (Wu et al., 2019; Xie et al., 2015; Yao et al., 2018). Survival analysis showed that high WWP1 expression was associated with worse prognosis and decreased 5-year survival rates, particularly in stage III and IV patients (Faber et al., 1998).

Moreover, in hepatocellular carcinoma (HCC), WWP2, another WWP family member, is frequently overexpressed, with higher levels correlating with tumor recurrence and lower survival rates. In ovarian cancer, WWP2 mutations significantly affect survival, with patients harboring WWP2 mutations exhibiting a median survival time of 12 months compared to 24 months in those without the mutation (Li Z et al., 2024).

In gastric cancer, elevated expression levels of both WWP1 and WWP2 are significantly associated with worse OS, particularly in early-stage tumors, suggesting a role for these proteins in the early metastatic spread of gastric cancer (Sluysmans et al., 2021).

In summary, the mutation status and RNA expression levels of WWP family members, particularly WWP1 and WWP2, are emerging as important prognostic factors in various cancers. High expression levels of WWP1 and WWP2 frequently correlate with poor prognosis, increased tumor invasiveness, and reduced survival rates in cancers such as breast, colorectal, lung, liver, and ovarian cancers. These findings underscore the potential of WWPs as biomarkers and therapeutic targets in cancer treatment.

Recent studies have identified upstream signaling pathways that regulate WWP1 expression (Figure 4). Various non-coding RNAs either upregulate or downregulate WWP1. For instance, in glioma tissues, decreased WWP1 levels correlated with increased miR-30a-5p and p65 phosphorylation levels, suggesting a negative correlation between WWP1 mRNA and miR-30a-5p expression. Notably, miR-30a-5p promoted glioma cell proliferation, migration, and invasion by targeting WWP1 (Zhao et al., 2019).

In patients with inflammatory bowel disease (IBD), increased levels of miR-16-5p and miR-21-5p (elevated in ulcerative colitis) suggested WWP1 as a target for these microRNAs, potentially contributing to IBD-associated colorectal cancer (CRC) (Zhou et al., 2021). In gastric cancer (GC), downregulated miR-129-5p and miR-129-3p were associated with WWP1 expression. Functional studies indicated that miR-129-5p binds to the coding sequence of WWP1 mRNA, inhibiting GC cell proliferation and migration in vitro and slowing tumor growth in vivo (Ma et al., 2019). Similarly, miR-584-5p inhibited GC cell proliferation and induced apoptosis by down-regulating WWP1 and activating the TGF-β signaling pathway (Li et al., 2017).

In prostate cancer (PCa), WWP1 is a direct target of miR-452, which is downregulated in PCa patients. Increased WWP1 expression negatively correlates with miR-452 levels, and miR-452 inhibits PCa cell proliferation and invasion by regulating WWP1 (Goto et al., 2016) (Table 1). These findings provide insights into the molecular mechanisms of cancer development and suggest potential therapeutic targets. Further research is required to explore the roles of WWP1 and its regulatory microRNAs in cancer pathogenesis and treatment.

The MYC gene is one of the most frequently dysregulated oncogenes implicated in the initiation, progression, and advancement of various cancers (Duffy et al., 2021). Research by Lee et al. demonstrated that MYC is enriched in the promoter region of WWP1, promoting its expression and identifying WWP1 as a potential MYC target gene. Additionally, phosphatase and tensin homolog (PTEN), a commonly mutated, deleted, or silenced tumor suppressor in numerous cancers, has been linked to the WWP1-PTEN axis in MYC-induced tumorigenesis and progression (Li et al., 1997; Bonneau and Longy, 2000; Lee et al., 2019).

Further studies showed that WWP1 is highly expressed in intrahepatic cholangiocarcinoma (ICC), with elevated levels correlating with poor prognosis. WWP1 targets NEDD4 family interacting protein 1 (NDFIP1) for ubiquitination, promoting ICC cell proliferation, migration, and invasion. Importantly, MYC drives WWP1 upregulation in ICC, enhancing WWP1 expression to support ICC cell growth and survival through NDFIP1 ubiquitination (Li et al., 2022) (Table 1). These findings deepen our understanding of the interactions among MYC, WWP1, and PTEN in cancer development, highlighting promising therapeutic targets for future cancer treatments.

The Hippo signaling cascade includes two key kinases, MST1/2 and LATS1/2, along with upstream components such as Merlin/NF2, FRMD, and KIBRA, which are crucial for pathway regulation (Yin et al., 2013; Xu et al., 2016; Swaroop et al., 2021). MST1/2, supported by SAV1, activates LATS kinases by phosphorylating LATS1/2 and its cofactor MOB1. Activated LATS1/2 then phosphorylates YAP and TAZ, resulting in their inhibition via cytoplasmic translocation or degradation. Specifically, TAZ phosphorylation promotes β-TrCP-mediated ubiquitination and subsequent proteasomal degradation.

TAZ, a transcriptional coactivator, is negatively regulated by the Hippo pathway (Wang et al., 2009). It is frequently overexpressed in breast cancer (BC), driving cell proliferation, migration, and invasion (Chan et al., 2008). WWP1 recognizes and interacts with KLF5, a transcription factor highly expressed in BC, via its WW domain, leading to KLF5’s ubiquitination and proteasomal degradation (Chen et al., 2005). Interestingly, TAZ disrupts this interaction, enhancing BC cell proliferation by preventing WWP1-mediated KLF5 degradation.

YAP, another coactivator and primary effector of the Hippo pathway, is overexpressed in various tumors, including BC (Tong et al., 2006). BRCA-associated protein-1 (BAP1), a deubiquitinating enzyme and tumor suppressor, regulates processes such as DNA repair and cell cycle control (Louie and Kurzrock, 2020). Studies have shown that WWP1 is underexpressed in melanoma, where KLF5 levels are elevated. BAP1 counteracts WWP1-mediated KLF5 ubiquitination, promoting melanoma development by stabilizing KLF5 within the BAP1/HCF-1 complex (Misaghi et al., 2009; Jia et al., 2021) (Table 1). This complex contributes to cell cycle progression by inhibiting p27 expression, thereby driving oncogenic effects in BC (Qin et al., 2015).

The epidermal growth factor receptor (EGFR) family, including ErbB4, plays critical roles in various cancers, notably breast cancer (BC) (Roskoski, 2014). ErbB4, a 180 kDa glycoprotein, features a ligand-binding extracellular region, a hydrophobic transmembrane domain, and a cytoplasmic region containing a tyrosine kinase domain (Omerovic et al., 2004). Research has shown that WWP1 specifically interacts with the ErbB4-CyT1 subtype, targeting it for ubiquitination-mediated degradation. This interaction involves WWP1’s first and third WW domains and ErbB4’s second PY motif. Notably, ErbB4 activates the tumor suppressor BRCA1 and reduces the proliferation and survival of breast epithelial cells (Muraoka-Cook et al., 2006). WWP1 reduces endogenous ErbB4 levels in BC cell lines, promoting cell proliferation and survival.

KLF5, a key member of the KLF family, is also targeted by WWP1, which interacts with its WW domain, leading to KLF5 degradation and suppressed BC cell proliferation (Li et al., 2009). WWP1 acts as a negative regulator of LATS1, a serine/threonine kinase and tumor suppressor. By binding to WWP1’s WW domains, LATS1 undergoes polyubiquitination and degradation via the 26S proteasome pathway (Visser and Yang, 2010), reducing LATS1 levels and enhancing BC cell proliferation (Yeung et al., 2013). These findings underscore WWP1’s multifaceted role in modulating key proteins involved in cancer progression.

TGF-β, a multifunctional cytokine, regulates cell proliferation, differentiation, survival, and apoptosis through various intracellular pathways (Kaminska et al., 2005). Smad transcription factors are central to TGF-β signaling and cancer progression (Massagué et al., 2005). WWP1 negatively regulates this pathway by ubiquitinating and degrading critical components like Smad2 and TβRI, which in prostate cancer (PCa) results in WWP1 overexpression that inhibits TGF-β-induced gene expression and promotes cell proliferation (Chen et al., 2007).

NDFIP1, an adaptor for NEDD4 family proteins, interacts with WWP1 and has potential anti-tumor effects. However, WWP1-mediated ubiquitination reduces NDFIP1 levels, promoting intrahepatic cholangiocarcinoma (ICC) cell proliferation and migration (Li et al., 2022). Similarly, RNF11, overexpressed in various tumors (Li et al., 2008; Wojciechowski et al., 2018), interacts with WWP1’s WW domains via its PY motif. While WWP1 ubiquitinates RNF11 in vitro and in vivo, it does not lead to RNF11 degradation or alter its localization. Instead, WWP1 modulates RNF11’s ability to downregulate ErbB2 and EGFR, highlighting its complex role in cancer biology (Chen et al., 2008; Zhi and Chen, 2012).

WWP1 negatively regulates the TGF-β tumor suppressor pathway by targeting components like Smad2 and TβRI for ubiquitination and degradation, thereby enhancing prostate cancer (PCa) cell proliferation (Massagué and Like, 1985). Notably, TβRI lacks a PY motif, yet WWP1 directly mediates its degradation. Additionally, WWP1 modifies PTEN, another key tumor suppressor that also lacks a PY motif, inhibiting its localization on the plasma membrane and impairing its ability to resist PI3K activation (Lee et al., 2019). This modification increases PI3K signaling, driving uncontrolled growth and drug resistance in tumor cells (Engelman et al., 2006; Song et al., 2012; Fruman et al., 2017; Song and Pandolfi, 2022). WWP1 employs K11 and K48 ubiquitin chains for degradation and adds K27 chains to PTEN, preventing its dimerization without causing degradation, ultimately supporting PCa cell survival.

p27, a key regulator that inhibits the cyclin E/CDK2 complex, also lacks a PY motif but is targeted by WWP1, which facilitates its lysine-48-linked ubiquitination (Cao et al., 2011). In acute myeloid leukemia (AML), elevated WWP1 expression reduces p27 levels, promoting cell cycle progression and enhancing AML cell survival (Sanarico et al., 2018). In liver cancer tissues, KLF14 expression is significantly downregulated, yet it accumulates at the VEPH1 promoter, enhancing VEPH1 transcription and protein expression. However, WWP1 ubiquitinates and degrades KLF14, which lacks a PY motif, suppressing VEPH1 expression and promoting liver cancer cell proliferation, invasion, and migration (Scohy et al., 2000; Zhang et al., 2024).

Additionally, the tumor suppressor protein p53 plays a critical role in cellular stress responses, facilitating growth arrest or apoptosis. WWP1 interacts with the DNA-binding domain of p53, and although the proline-rich domain of p53 lacks a PY motif, it enhances protein-protein interactions. WWP1 ubiquitinates p53 via an E3 ligase-dependent mechanism, promoting its nuclear export and inhibiting apoptosis, thus contributing to tumor progression (Laine and Ronai, 2007; Cheng et al., 2014).

This section explores the regulatory mechanisms controlling upstream modulators and downstream targets, highlighting their roles in proliferation, apoptosis, cell cycle progression, migration, and invasion. These findings underscore the significance of WWP1 in cancer biology (Figure 4).

Glioma, originating from glial or precursor cells, accounts for 80% of malignant tumors in the central nervous system (CNS). Despite surgical resection, radiotherapy, and chemotherapy, patient prognosis remains poor, underscoring the need for novel treatment strategies (Zhang et al., 2021; Wei et al., 2023). Studies suggest that miR-30a-5p promotes glioma cell growth and invasion. Research by Zhao et al. indicated that WWP1 inhibits NF-κB activation, a pathway linked to glioma formation, and is downregulated in glioma tissues, possibly targeted by miR-30a-5p (Wang et al., 2015; Park et al., 2020) (Figure 5A). The Wnt/β-catenin pathway activates miR-30a-5p, which directly binds to β-catenin/TCF4. In glioma cell lines (U87, U251), decreased WWP1 mRNA levels correlate with increased miR-30a-5p and phosphorylated p65 levels. Overexpression of WWP1 reduces NF-κB p65 phosphorylation, while NF-κB p65 overexpression enhances miR-30a-5p via direct binding to its promoter, forming a positive feedback loop in the “miR-30a-5p-WWP1-NF-κB” signaling axis (Zhao et al., 2019).

Although these findings suggest a potential role for WWP1 in glioma development and indicate its promise as a therapeutic target, further direct experimental evidence is required to confirm its causal involvement in glioma progression. The potential for targeting WWP1 in glioma therapy remains a promising area for future investigation.

Melanoma, originating from the malignant proliferation of epidermal melanocytes, constitutes only 1% of skin tumors (Cronin et al., 2018), emphasizing the importance of early detection and treatment to reduce mortality (Neila and Soyer, 2011; Saamarthy et al., 2024). Autophagy has been identified as a mechanism that inhibits precancerous cell proliferation, presenting itself as a potential therapeutic target for melanoma (Gozuacik and Kimchi, 2004; Liu et al., 2013; Jia et al., 2019). Studies on various melanoma cell lines (CRL-2208, HTB-65, ACC236) reveal low WWP1 expression alongside high KLF5 levels, which correlate with poor prognosis. This interaction suppresses autophagy while enhancing melanoma migration and invasion, suggesting an essential role for the WWP1-KLF5-BAP1 axis in melanoma progression (Jia et al., 2021) (Figure 5B).

Although these findings underscore the potential involvement of WWP1 in melanoma, further experimental validation is necessary to establish a causal relationship between WWP1 expression and melanoma progression. These insights highlight promising therapeutic targets for addressing this aggressive form of skin cancer.

Primary liver cancer is histologically classified into hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The development of liver cancer is driven by complex pathological mechanisms, including hepatitis infection, alcohol-induced cirrhosis, and dietary factors (Massarweh and El-Serag, 2017; Salazar and Le, 2021). ICC, a highly aggressive and lethal primary hepatobiliary tumor, exhibits poor prognosis and rising global incidence (Joob and Wiwanitkit, 2017). ICC is now recognized as the second most prevalent liver malignancy following HCC (Huang et al., 2021). Literature indicates that the proto-oncogene MYC enhances WWP1 expression (Ambrozkiewicz et al., 2018). MYC-induced upregulation of WWP1 promotes NDFIP1 ubiquitination, contributing to ICC progression (Li et al., 2022) (Figure 5C). Given its pivotal role in ICC pathogenesis, WWP1 serves as a potential prognostic marker and therapeutic target for ICC.

HCC, one of the most prevalent cancers worldwide, is marked by significantly elevated WWP1 protein levels in tumor tissues compared to adjacent non-cancerous tissues. Cheng et al. demonstrated that silencing WWP1 suppresses HCC cell proliferation and activates Caspase 3 and p53, critical mediators of apoptosis that promote programmed cell death in HCC cells (Laine and Ronai, 2007; Cheng et al., 2014). Additionally, KLF14 accumulates on the VEPH1 promoter, enhancing transcription and protein production. However, WWP1-mediated post-translational modifications suppress VEPH1 expression, potentially driving liver cancer cell proliferation, invasion, and migration (Zhang, Wang et al., 2024) (Figure 5D).

While these findings suggest a role for WWP1 in HCC progression, further experimental validation is needed to confirm its precise mechanisms and therapeutic potential in HCC treatment.

PTC is the most common endocrine malignancy and a leading cause of death among malignant tumors (Turan and Erkılıç, 2023). Current treatments for PTC primarily include surgery along with various alternative therapies (Garcia-Alvarez et al., 2022). Research has shown that WWP1, recognized as a multifunctional protein in PTC, is highly expressed in PTC tissues and cell lines. In PTC cell lines such as Nthy-ori3-1, NPA87, and KAT-5, WWP1 knockout led to increased PTEN levels, resulting in reduced p-PI3K and p-AKT levels. In B-CPAP and TPC-1 cells treated with si-WWP1, the expression levels of CyclinD1, CyclinE1, CDK2, CDK4, and CDK6 were suppressed, while p21 expression significantly increased. Conversely, WWP1 overexpression yielded the opposite effects, promoting PTC cell proliferation and preventing cell cycle arrest (Wang et al., 2022) (Figure 5E). These findings suggest that WWP1 exerts oncogenic effects in PTC cells, making it a potential therapeutic target for PTC treatment.

AML is a blood cancer characterized by distinct genetic mutations (Xia et al., 2023). Its high heterogeneity contributes to frequent relapses, emphasizing the need for targeted therapies (Lin et al., 2022; Nelles et al., 2023). WWP1’s role in AML is modulated through its protein substrates, including p27, p53, and Smads (Peschiaroli et al., 2010; Cao et al., 2011). Specifically, WWP1 inactivation increases p27 levels, inducing cell cycle arrest in AML cells and impairing the malignant potential of bone marrow cells. Additionally, WWP1 inactivation promotes the conversion of cytoplasmic LC3-I to lipid-bound LC3-II, a key marker of autophagosome membrane formation (Klionsky et al., 2016). In AML cells, LC3-I and p62/SQSTM1 levels increased, while LC3-II and ATG7 levels decreased, leading to autophagy inhibition (Sanarico et al., 2018) (Figure 5F). These findings suggest that WWP1 may be a promising therapeutic target for AML, although further studies are necessary to elucidate its mechanisms and develop effective targeted treatments.

In the Hippo signaling pathway, MST1/2, assisted by its cofactor SAV1, enhances LATS kinase activity by phosphorylating LATS1/2 and the LATS cofactor MOB. Activated LATS1/2 phosphorylates YAP and TAZ, inhibiting their function by promoting their cytoplasmic translocation or degradation (Kanumuri et al., 2021). Research indicates that TAZ/YAP can counteract WWP1-mediated KLF5 degradation, thereby promoting breast cancer cell proliferation and tumor development (Figure 5G). WWP1-mediated ubiquitination contributes to the degradation of LATS1, regulating BC cell proliferation by reducing LATS1 levels (Yeung et al., 2013).

Additionally, WWP1 acts as an inhibitor of bone metastasis in MDA-MB-231 BC cells. Inhibiting WWP1 substantially decreases CXCL12-induced CXCR4 lysosomal transport and degradation, leading to an increased number of osteolytic lesions and metastatic sites (Benovic and Marchese, 2004; Bohn et al., 2009). These findings suggest that factors influencing WWP1 expression or activity could alter the metastatic potential of BC cells to bone (Nguyen Huu et al., 2008).

OS, a malignant tumor arising from mesenchymal tissue, is the most common primary malignancy of the human skeletal system. It typically presents at advanced stages, exhibits high early metastasis rates, and demonstrates resistance to chemotherapy, resulting in low cure rates (Wang et al., 2024). Wu et al. reported that WWP1 mRNA expression was elevated in 88% of OS tissues compared to adjacent non-cancerous tissues, suggesting an oncogenic role for WWP1 in OS. Moreover, WWP1 overexpression increased MMP2 and MMP9 activity, proteins associated with tumor metastasis and angiogenesis. WWP1 also promotes OS cell invasion by modulating MMP2 and MMP9 activity and inducing epithelial-mesenchymal transition (EMT) (Schmalhofer et al., 2009; Wu et al., 2015) (Figure 5H). These findings highlight the potential role of WWP1 in OS pathogenesis and progression, but further studies are required to confirm its precise role and therapeutic potential in OS treatment.

PCa poses a significant public health challenge in developed nations, ranking as the second most common cancer among men and a leading cause of cancer-related deaths in older males (Albertsen, 2020; Zhou et al., 2024). Research has identified the WWP1 gene on chromosome 8q21, a region frequently amplified in various cancers, including PCa, suggesting that WWP1 may function as an oncogene in PCa. WWP1 overexpression has been observed in up to 60% of PCa xenografts and cell lines, such as the 22Rv1 PCa cell line. Studies revealed that WWP1 facilitates the degradation of key components of the TGF-β signaling pathway, thereby enhancing cell proliferation by inhibiting TGF-β signaling (Chen et al., 2007).

Another study demonstrated that miR-452 expression is significantly reduced in PCa tissues, while WWP1 is overexpressed. miR-452 inhibits PCa cell migration and invasion by downregulating WWP1 expression (Goto et al., 2016) (Figure 5I). These findings suggest that WWP1 may serve as a therapeutic target for PCa detection and treatment. However, further studies are necessary to fully elucidate its mechanisms and confirm its potential as a clinical target for PCa therapy.

GC is a highly prevalent malignancy, and despite advancements in treatment, survival rates for patients with advanced GC remain low, particularly among those experiencing metastasis, recurrence, or chemotherapy (Yang et al., 2023). Recent studies have implicated the NEDD4-like protein family in cancer progression through PTEN reduction and AKT signaling promotion in tumor cells (Wang et al., 2007). The PTEN/AKT pathway is crucial in oncogenic signaling across various cancer types (Cheng et al., 2008). WWP1 has been shown to ubiquitinate PTEN, increasing p-AKT levels and promoting GC cell growth and proliferation (Zhang et al., 2015).

Furthermore, dysregulated oncogenic and tumor-suppressor miRNAs play essential roles in processes such as cell proliferation, apoptosis, invasion, angiogenesis, and drug resistance in tumors (Song and Ajani, 2013). Using bioinformatics tools such as TargetScan and miRCode, miR-129-5p and miR-129-3p were identified as potential WWP1 regulators (Lewis et al., 2003; Jeggari et al., 2012). Research indicates that these miRNAs suppress WWP1, thereby inhibiting GC cell survival (Ma et al., 2019). Another study revealed a negative correlation between miR-584-5p levels and WWP1 expression in GC tissues and cell lines, with miR-584-5p suppressing GC cell proliferation by downregulating WWP1 (Li et al., 2017) (Figure 5J). These findings highlight WWP1 as a promising target for GC treatment and prognosis, offering valuable insights for novel therapeutic development.

CSCC is a growing global health concern, with increasing incidence rates and a high propensity for invasion, metastasis, and recurrence (Kivisaari and Kähäri, 2013; Wang et al., 2021). Xi et al. reported that WWP1 mRNA and protein levels were significantly elevated in SCL-1 and A431 cells compared to normal tissues. WWP1 depletion resulted in reduced levels of MMP-2, cyclin D1, and Bcl-2, leading to G0/G1 phase cell cycle arrest. JAK is identified as an upstream kinase of STAT3, and WWP1 enhances CSCC cell proliferation by modulating total STAT3 and p-STAT3 levels, thereby activating the STAT3 signaling pathway (Xia et al., 2018; Xu et al., 2022) (Figure 5K).

These findings suggest that WWP1 may serve as a potential molecular target for CSCC treatment. However, further investigation is needed to fully understand the mechanisms through which WWP1 exerts its influence and to validate these preliminary results. These insights could pave the way for therapeutic strategies, but additional studies are required to confirm WWP1’s role as a reliable molecular target for CSCC diagnosis, prognosis, and treatment.

CRC is one of the leading causes of cancer-related mortality globally (Aguiar Junior et al., 2020). Despite advancements in screening and preventive measures, CRC remains a significant health challenge due to its high incidence (Villéger et al., 2018). Research demonstrates that transfecting an overexpression plasmid of WWP1 into CRC SW480 cells induces a dose-dependent increase in WWP1 protein levels. Studies suggest that NEDD4, a specific E3 ligase for PTEN, reduces PTEN levels through polyubiquitination (Wu et al., 2003; Trotman et al., 2007), thereby activating the AKT signaling pathway (Trotman et al., 2007). Similarly, WWP1 elevates p-AKT levels by ubiquitinating PTEN in CRC, promoting CRC cell proliferation and metastasis (Chen and Zhang, 2018) (Figure 5L). These findings highlight the significant role of WWP1 in CRC, suggesting its potential as a novel target for CRC diagnosis and treatment. This research lays the foundation for developing future therapeutic strategies centered on protein ubiquitination and antitumor activity stimulation.