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Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin β4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes. Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/β subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFβ, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance. This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. 5QcBi13X1fvDcm9V-b6ZkU Video Abstract

Ubiquitination is one of the most important post‐translational modifications which plays a significant role in conserving the homeostasis of cellular proteins. In the ubiquitination process, ubiquitin is conjugated to target protein substrates for degradation, translocation or activation, dysregulation of which is linked to several diseases including various types of cancers. E3 ubiquitin ligases are regarded as the most influential ubiquitin enzyme owing to their ability to select, bind and recruit target substrates for ubiquitination. In particular, E3 ligases are pivotal in the cancer hallmarks pathways where they serve as tumour promoters or suppressors. The specificity of E3 ligases coupled with their implication in cancer hallmarks engendered the development of compounds that specifically target E3 ligases for cancer therapy. In this review, we highlight the role of E3 ligases in cancer hallmarks such as sustained proliferation via cell cycle progression, immune evasion and tumour promoting inflammation, and in the evasion of apoptosis. In addition, we summarise the application and the role of small compounds that target E3 ligases for cancer treatment along with the significance of targeting E3 ligases as potential cancer therapy. E3 ubiquitin ligases are important players in cellular processes by ubiquitinating substrate proteins in disease progression such as cancer. Owing to this, scientists attempt to identify safe and bioavailable compounds targeting E3 ligases. In this review, we summarise the roles of E3 ligases in cancer‐related pathways, highlight the application and clinical significance of small molecule inhibitors and discuss further directions .

Melanoma, a highly aggressive skin cancer with limited therapeutic options, demonstrates poor prognosis in advanced stages. Tripartite motif-containing 22 (TRIM22), an E3 ubiquitin ligase of the tripartite motif (TRIM) family, is implicated in tumorigenesis, but its working mechanism remains poorly understood in melanoma. In this study, we found that expression of TRIM22 was abnormally upregulated in melanoma tissues, correlating with tumor stages. Functional analysis demonstrated that TRIM22 promoted melanoma cell proliferation in vitro. Furthermore, we found that in malignant melanoma, TRIM22 expression is negatively correlated to the level of p21, an inhibitor of cell cycle. With quantitative real-time PCR (qRT-PCR) assay and cycloheximide (CHX) treatment, we confirmed that TRIM22 suppressed p21 expression at protein level. Via S-Protein pull-down assay, we found that p21 could interact with TRIM22 at the SPRY domain. A ubiquitination assay proved that TRIM22 promoted the K63-linked ubiquitination of p21, and thereby induced p21 degradation through the proteasome pathway to accelerate cell cycle progression. Moreover, we discovered that overexpression of TRIM22 could not bring further boost of cell proliferation in p21 knockdown melanoma cells, indicating an epistatic role of p21 to TRIM22. Overall, our findings elucidated that TRIM22 acted as an E3 ligase targeting p21 for degradation to promote melanoma progression, which improved the understanding of TRIM22 function and provided more clues for developing TRIM22 as a potential target for malignant melanoma treatment.

Metabolic homeostasis is essential for cellular function in living organisms. In cancer cells, metabolic processes are reprogrammed to meet the energy demands and biosynthetic needs for rapid growth. This reprogramming enhances nutrient flux through the glycolytic pathway, supporting ATP production and branching into pathways that synthesize macromolecules required for cell proliferation. One critical branching pathway is the hexosamine biosynthesis pathway (HBP), which, driven by metabolic reprogramming, facilitates the synthesis of uridine-5’-diphospho-N-acetylglucosamine (UDP-GlcNAc), a glycosylation substrate. This pathway is regulated by the rate-limiting enzyme glutamine-fructose-6-phosphate transaminase (GFPT), a key controller of cellular UDP-GlcNAc levels and protein glycosylation. Dysregulation of GFPT is linked to metabolic disorders, like in diabetes, and it is also frequently upregulated in cancers. Given that GFPT plays a pivotal role in cancer metabolism, elucidating its regulatory interactions with other metabolic signaling pathways under metabolic stress is crucial to identifying therapeutic vulnerabilities in cancer. This review discusses the interaction network of GFPT with other metabolic pathways, its role in nutrient sensing, and the implications of GFPT deregulation in cancer.