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Understanding Heparan Sulfate Biosynthesis and Functional Implications of Heparanase
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) proteoglycans are present on the plasma membrane of all animal cells studied so far and are a major component of extracellular matrices. Heparanase is an endo-ß-glucuronidase that cleaves HS chains at internally located ß-glucuronidic linkages1. Except its conventional enzymatic function, non-enzyme function and its function in the nucleus have been demonstrated recently.

Regulation of HS biosynthesis has long been a myth. By generating HEK293 cells that overexpress different doses of C5-epimerase and a mutant without catalytic activity we created tools to analyze HS chain structure. We show that HS chain length increases in a dose dependent manner, dependent on the enzymatic activity of C5-epimerase, which can be reversed by co-overexpresssing with 2-O-sulfotransferase.

Lipoprotein lipase (LpL) is a HS-bound enzyme that processes the triglycerides of lipoproteins from both exogenous and endogenous sources. Underdeveloped adipose tissue was revealed in heparanase transgenic mice, due to compromised LpL activity. Mechanistically, a likely possibility was demonstrated due to HS shedding related to overexpressed heparanase.

The finding that breast cancer T47D cells which overexpress heparanase adopt a higher rate of aerobic glycolysis fueling cell proliferation and cell survival added up to the diverse functions of heparanase.

Transcriptomic analysis after knockdown of heparanase in melanoma cells confirmed involvement in inflammatory responses as studied previously, and regulation of cell adhesion, ECM components, apoptosis and nucleosome assembly emerged as novel functional and mechanistic indications of heparanase. Supported by experimental evidence, heparanase’s effect in cell adhesion and apoptosis validated its role in cancer progression. Moreover, regulation of nucleosome assembly prompts further investigation into its action mode in the nucleus.

Taken together, the present study adds to the elucidation of HS biosynthesis and depicts novel roles of heparanase, highlighting its multifaceted roles in cancer and providing exciting notions for future studies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 44
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1517
Keywords [en]
Heparan sulfate, biosynthesis, heparanase, lipid metabolism, cancer, cell adhesion, apoptosis.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-366109ISBN: 978-91-513-0508-0 (print)OAI: oai:DiVA.org:uu-366109DiVA, id: diva2:1263761
Public defence
2019-01-23, A1:111a, Husargatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2019-01-09 Created: 2018-11-16 Last updated: 2019-02-14
List of papers
1. Enzyme overexpression - an exercise toward understanding regulation of heparan sulfate biosynthesis
Open this publication in new window or tab >>Enzyme overexpression - an exercise toward understanding regulation of heparan sulfate biosynthesis
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31242Article in journal (Refereed) Published
Abstract [en]

Biosynthesis of heparan sulfate (HS) involves conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) units catalyzed by glucuronyl C5-epimerase (Hsepi). IdoA units are the favored substrate for 2-O-sulfotransferase (2OST). We used HEK293 cells as a model to investigate the effects of overexpression of these enzymes on HS structure. Overexpression of Hsepi alone resulted in an unexpected increase in HS chain length. A Hsepi point-mutant (Y168A), devoid of catalytic activity, failed to affect chain length. Moreover, the effect of Hsepi overexpression on HS chain length was abolished by simultaneous overexpression of 2OST. These findings raise novel aspects on regulation of HS biosynthesis. We propose a hypothetical enzyme-binding protein (EBP) with distinct, specific and partly overlapping binding sites, the interactions of which will determine levels of enzymes available to the biosynthetic process.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-303052 (URN)10.1038/srep31242 (DOI)000381201900001 ()27511124 (PubMedID)
External cooperation:
Funder
Swedish Research Council, 2015-02595Swedish Cancer Society, 150815The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IB2012-4524Swedish Heart Lung Foundation, 20140131
Available from: 2016-09-14 Created: 2016-09-14 Last updated: 2018-11-16Bibliographically approved
2. Heparanase disrupts Lipoprotein lipase function in heparanase transgenic mice.
Open this publication in new window or tab >>Heparanase disrupts Lipoprotein lipase function in heparanase transgenic mice.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-366324 (URN)
Available from: 2018-11-19 Created: 2018-11-19 Last updated: 2018-11-20
3. Heparanase modifies glucose metabolism in breast cancer T47D cells.
Open this publication in new window or tab >>Heparanase modifies glucose metabolism in breast cancer T47D cells.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-366106 (URN)
Available from: 2018-11-16 Created: 2018-11-16 Last updated: 2018-11-16
4. Transcriptomic analysis reveals multifaceted roles associated with heparanase expression in melanoma cells.
Open this publication in new window or tab >>Transcriptomic analysis reveals multifaceted roles associated with heparanase expression in melanoma cells.
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-366102 (URN)
Available from: 2018-11-16 Created: 2018-11-16 Last updated: 2018-11-16

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