Hyaluronan Synthase 1: A Mysterious Enzyme with Unexpected Functions

Abstract

Hyaluronan synthase 1 (HAS1) is one of three isoenzymes responsible for cellular hyaluronan synthesis. Interest in HAS1 has been limited because its role in hyaluronan production seems to be insignificant compared to the two other isoenzymes, HAS2 and HAS3, which have higher enzymatic activity. Furthermore, in most cell types studied so far, the expression of its gene is low and the enzyme requires high concentrations of sugar precursors for hyaluronan synthesis, even when overexpressed in cell cultures. Both expression and activity of HAS1 are induced by pro-inflammatory factors like interleukins and cytokines, suggesting its involvement in inflammatory conditions. Has1 is upregulated in states associated with inflammation, like atherosclerosis, osteoarthritis, and infectious lung disease. In addition, both full length and splice variants of HAS1 are expressed in malignancies like bladder and prostate cancers, multiple myeloma, and malignant mesothelioma. Interestingly, immunostainings of tissue sections have demonstrated the role of HAS1 as a poor predictor in breast cancer, and is correlated with high relapse rate and short overall survival. Utilization of fluorescently tagged proteins has revealed the intracellular distribution pattern of HAS1, distinct from other isoenzymes. In all cell types studied so far, a high proportion of HAS1 is accumulated intracellularly, with a faint signal detected on the plasma membrane and its protrusions. Furthermore, the pericellular hyaluronan coat produced by HAS1 is usually thin without induction by inflammatory agents or glycemic stress and depends on CD44–HA interactions. These specific interactions regulate the organization of hyaluronan into a leukocyte recruiting matrix during inflammatory responses. Despite the apparently minor enzymatic activity of HAS1 under normal conditions, it may be an important factor under conditions associated with glycemic stress like metabolic syndrome, inflammation, and cancer.

Striae reconstructed, a full thickness skin model that recapitulates the pathology behind stretch marks

“…On the other hand, we found increased inflammatory mediators such as CXCL8 (190%), TNF‐α (417%) and HAS1 (458%) on SD‐HDF. This is not surprising since, unlike HAS2 and HAS3, HAS1 is fundamentally involved in the inflammatory processes . As expected from previous reports comparing cell cultures of HDF from rubrae and albae lesions , we detected a 42% decrease in α‐SMA (ACTA2) expression in SD‐HDF, which were isolated from a striae albae lesion.…”

Hyaluronic acid synthase 2 promotes malignant phenotypes of colorectal cancer cells through transforming growth factor beta signaling

“…44 Several studies suggest that intracellular hyaluronan and HAS are involved in physiological events or conditions such as inflammation or cancer. 45,46 In agreement with these studies, we anticipate intracellular HAS2 to be related with CRC malignancy regulation. Furthermore, HAS2 has a multi-pass membrane bound enzyme structure and may interact with other cytoplasmic proteins such as protein kinase C that are involved in TGF-β signaling.…”

“…However, SMAD2 activation showed a more dramatic response in the CRC samples and SMAD2 has been reported to be correlated with CRC malignancy . Several studies suggest that intracellular hyaluronan and HAS are involved in physiological events or conditions such as inflammation or cancer . In agreement with these studies, we anticipate intracellular HAS2 to be related with CRC malignancy regulation.…”

A guide to hyaluronan and related enzymes in breast cancer: biological significance and diagnostic value

“…Hyaluronan content is known to be increased in many cancers and rapidly remodeling tissues in general, and this may be partially due to altered HAS expression . Contrary to previous beliefs, HAS protein is not only increased in tumor‐interacting stromal cells (HAS1, HAS2, HAS3) but also in carcinoma cells (only HAS1), as it was demonstrated by immunostainings in a study which evaluated 278 breast cancer cases.…”