The HYAL1 paradox in cancer: From complex tumor biology to novel therapeutic strategies
Year: 2025
Type: article
Abstract: • Dual-Functionality of HYAL1 : HYAL1 exhibits paradoxical roles in cancer, acting as both a tumor promoter (e.g., in prostate, esophageal, and osteosarcoma) and a tumor suppressor (e.g., in colorectal cancer), highlighting its context-dependent nature. • Mechanistic Complexity : HYAL1 influences tumor progression through multiple pathways, including HA degradation, endocytosis enhancement, MMP/TIMP balance regulation, integrin activation, and cytoskeletal reorganization. • Epigenetic Regulation : HYAL1 expression is directly regulated by epigenetic factors such as BRD2, revealing a novel layer of transcriptional control in cancers like pancreatic ductal adenocarcinoma. • Therapeutic Potential : HYAL1-expressing oncolytic viruses demonstrate significant promise in remodeling the tumor microenvironment, enhancing drug penetration, and improving the efficacy of chemotherapy and immunotherapy. • Biomarker and Diagnostic Value : HYAL1 serves as a prognostic biomarker in multiple cancers (e.g., bladder, oral, and colorectal cancer) and is detectable in serum and urine, supporting its clinical utility. Hyaluronidase 1 (HYAL1), a key enzyme in hyaluronic acid (HA) metabolism, exhibits a perplexing paradoxical character in tumor biology. This review systematically delineates the dual roles of HYAL1 in cancer: on one hand, by degrading HA to generate low-molecular-weight fragments with pro-angiogenic and immunomodulatory activities, HYAL1 promotes tumor progression and metastasis in various malignancies, including prostate cancer, esophageal carcinoma, and osteosarcoma; on the other hand, it demonstrates tumor-suppressive properties in specific contexts such as colorectal cancer models. This functional contradiction underscores the context-dependent nature of HYAL1, whose activity and effects are profoundly influenced by tumor type, microenvironmental features, and epigenetic regulation. Mechanistically, HYAL1 functions not only through the classical HA-CD44 signaling axis but also by regulating the MMPs/TIMPs balance, integrin activation, and cytoskeletal reorganization. Recent studies reveal that HYAL1 expression is directly controlled by epigenetic regulators like BRD2, while its activity can be monitored in real-time using novel bioluminescent probes, providing powerful tools for investigating its dynamic functions. Notably, HYAL1-based therapeutic strategies have shown considerable promise, particularly in oncolytic virotherapy, where HYAL1-expressing recombinant viruses significantly enhance the penetration and efficacy of chemotherapeutic agents and immune cells within tumors. Key challenges persist, including HA metabolic complexity, functional redundancy among hyaluronidases, and HA fragment instability. Future research must decipher HYAL1′s context-specific roles within tumor heterogeneity, elucidate its epigenetic regulation, and develop targeted strategies. A deeper understanding of this HYAL1 paradox is essential to leverage its potential for precision cancer therapies targeting HA metabolism.
Source: Translational Oncology
Authors: Yun Jin, Tongyu Wang, Junyan Ma, Jiao Quan, Ning Zhou
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,390
OpenAlex ID: W4417483832