HAS2 (hyaluronan synthase 2)

2009-03-01   Diogo Escudero 

University of Miami School of Medicine, Miami, Florida 33136, USA


Atlas Image
HAS2 gene presented in the minus strand of chromosome 8.



Three independently expressed hyaluronan synthase genes have been identified in the human genome. HAS2 is present in chromosome 8q24.12, while HAS1 and HAS3 have been identified to loci 19q13.4 and 16q22.1 respectively.


The HAS2 gene encodes for a 552 amino acid product comprised of 4 exons. Translation starts at the first nucleotide of exon 2 while a discrete 5-untranslated region (UTR) is formed in exon 1.


Hyaluronan is catalyzed by three membrane-embedded HA synthases, although HAS2 is the only essential gene. The isozymes are coded by 3 separate genes that, although related, are unlinked in the chromosome. Regulation occurs at transcription, post-translational levels, as well as, by alternative splicing, differential sub-cellular localization and epigenetic processes. Hyaluronan deposits in the extracellular matrix have been associated with a variety of cellular processes such as motility, adhesion, division, morphogenesis, wound healing and vascular development. HAS2 overexpression, as well as, amplification of locus 8q24.12, has been implicated in tumor proliferation and metastasis in genitourinary tumors. Recently, the degree to which HA synthases can overexpressed has suggested the likelihood the gene may play contradicting roles as tumor suppressor and oncogene.



HAS2, a member of the glycosyl transferase family 2 proteins, is a multipass transmembrane protein that catalyses the polymerization of the integral extrecellular matrix component Hyaluronic acid from intracellular UDP-esterified precursor, resulting in glucuronic acid and N-acetylglucosamine dissacharide motifs.
Atlas Image
Illustration of HAS multipass transmembrane isozymes and their products.


HAS2 is one of the three characterized HA synthases responsible for the polymerization of Hyaluronic Acid in the extracellular matrix and is the only essential gene of the family. Although all three isozymes are equally capable of synthesizing HA polymers, it has been shown that HAS2 is the main HA synthase polymerizing long hyaluronan chains of MW ~2x106 Daltons.


The extent of HAS2 expression and catalytic activity has been linked to specific interactions between the extracellular hyaluronan and the HA receptors, CD44 and RHAMM, distributed in the plasma membrane. The underlying signaling pathways regulating HAS2 expression have not been fully characterized. A number of distinctively regulated factors have been associated with HA deposition and HAS2 expression such as IL-1beta, NF-kappaB, all-trans-Retinoic Acid, SP1, Ras, TGF-beta1 among many others.


HAS2 is localized in the plasma membrane as a multipass transmembrane protein. Although it has been suggested the human HAS2 may share the same proposed topological domains as its bacterial counterpart, the extent to which this statement trully represents its actual architecture has not yet been shown.


Hyaluronan synthase 2 is responsible for the synthesis and deposition of hyaluronan in the extracellular matrix. HAS2 is a member of the glycosyl transferase 2 protein family and catalyses the addition of UDP-esterified residues, to form glucuronic acid and N-acetylglucosamine dissacharide motifs present in HA molecules. Interactions between plasma membrane embedded HA receptors with hyaluronan in the cellular matrix have been suggested to either induce or repress HAS2s catalytic activity. The presence of hyaluronan in the extracellular matrix has been linked to a great number of vital cellular processes such cell division, motility and morphogenesis, among many others. HAS2 is either an oncogene or a tumor suppressor depending on the concentration and length of HA products deposited in the extracellular matrix. Long HA chains of high molecular weight in high concentrations have been linked with supressing angiogenesis and tumor proliferation, whereas 2-3 fold HAS2 overexpression has been implicated in the proliferation and metastasis in various genitourinary tumor types.


A total of 3 mammalian HAS genes have been isolated and identified (HAS1, HAS2, HAS3). Although they share similar amino acid sequences and structural conformations, each isozyme present different spacial and temporal expression patterns, molecular stability, kinetic properties and ability of yielding hyaluronan chains different in length and concentration.



Developmental studies have described mutations disrupting HAS2 synthesis as embryonic lethal. Such mutations prevent cardiac endothelial to mesenchymal transition, resulting in failed heart morphogenesis.

Implicated in

Entity name
Various cancer
Studies dating over 50 years have suggested an association between the increasing deposition of HA and tumors. Because hyaluronan is associated with such a variety of important biological cellular processes, it has been suggested that the abnormal overexpression of HAS2, among the other HA synthases, as well as deposition of HA in the extracellular matrix account for hijacked pathways to stimulate cell growth, proliferation, angiogenesis and metastasis in cancer cells. The use of pharmacological agents affecting HAS2 activity, as well as, HA breakdown in cancer treatment are promising. Recent studies suggest that tumor cells become less aggressive and proliferative when HA synthase is being suppressed or overexpressed in high concentrations. Diagnostic tests have been developed assaying for concentration of deposited hyaluronan as a tumor marker. The HA-Hase test, for example, is a sensitive and accurate diagnostic test for bladder cancer measuring the concentrations of hyaluronan and hyaluronidase (HA degrading protein) present in urine samples.
Dysfunctional expression of HAS2 has been published in many genitourinary tumors, such as prostate cancer, testicular cancer and bladder cancer. This altered expression has been linked with chromosomal locus 8q24 amplification as well as deregulated HAS2 transcription, which have been shown to follow tumor progression.
Histological studies, using specific hyaluronan affinity probes, suggest that all human epithelial tumors are associated with elevated amounts of hyaluronan in the extracellular matrix. Consequently, overexpression of HAS2 has been observed in various types of cancer. The presence of tumor associated hyaluronan has been observed in prostate cancer cells of high Gleason scores and matastasis, indicating poor prognosis. Also, primary tumor invasiveness and elevated PSA recurrence after surgical tumor removal have been correlated with strong stromal hyaluronan staining in radical prostatectomy specimens.
Entity name
Vascular disease
Changes in the concentration and cellular distribution of HA have been observed in vascular diseases such as atherosclerosis, restenotic lesion.
Increasing severity in athrosclerosis has been linked with decreasing concentration of hyaluronan distribution. Yet, the role HA may be playing during earlier phases of the disease is yet to be determined due to difficulty in early detection of the disease. Decreased HAS2 activity is stipulated to be playing a possible role in this matter.


Pubmed IDLast YearTitleAuthors
109304382000Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.Camenisch TD et al
156775522005Regulation of hyaluronan synthase-2 expression in human intestinal mesenchymal cells: mechanisms of interleukin-1beta-mediated induction.Ducale AE et al
104551881999Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties.Itano N et al
117173182002Hyaluronan-cell interactions in cancer and vascular disease.Toole BP et al
149884102004Identification and analysis of the promoter region of the human hyaluronan synthase 2 gene.Monslow J et al
173077352007Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB.Saavalainen K et al
185086142008Hyaluronan and hyaluronidase in genitourinary tumors.Simpson MA et al
157655042005Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns.Tien JY et al

Other Information

Locus ID:

NCBI: 3037
MIM: 601636
HGNC: 4819
Ensembl: ENSG00000170961


dbSNP: 3037
ClinVar: 3037
TCGA: ENSG00000170961


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Metabolism of carbohydratesREACTOMER-HSA-71387
Glycosaminoglycan metabolismREACTOMER-HSA-1630316
Hyaluronan metabolismREACTOMER-HSA-2142845
Hyaluronan biosynthesis and exportREACTOMER-HSA-2142850


Pubmed IDYearTitleCitations
221139452012Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells.66
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
176111972007Involvement of hyaluronan in regulation of fibroblast phenotype.59
173151942007Silencing of hyaluronan synthase 2 suppresses the malignant phenotype of invasive breast cancer cells.47
205225582010Proinflammatory cytokines induce hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway.38
209605092011Association of hyaluronic acid family members (HAS1, HAS2, and HYAL-1) with bladder cancer diagnosis and prognosis.38
220163932011Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1).38
225292142012Dynamic changes in cervical glycosaminoglycan composition during normal pregnancy and preterm birth.35
213574212011The human hyaluronan synthase 2 (HAS2) gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell.32
157223432005The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene.31


Diogo Escudero

HAS2 (hyaluronan synthase 2)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/412/has2