The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

Abstract

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer Mao, X.; Gauche, C.; Coughtrie, M. W. H.; Bui, C.; Gulberti, S.; Merhi-Soussi, F. Citation for published version (APA):Mao, X., Gauche, C., Coughtrie, M. W. H., Bui, C., Gulberti, S., Merhi-Soussi, F., ... Fournel-Gigleux, S. (2016). The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer. Oncogene, 35, 5043-5055. DOI: 10.1038/onc.2016 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3--O--sulfotransferase 3--OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3--OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in HER2--positive (HER2+) SKBR3 cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3--OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3--OST3A exerted dual activities acting as tumor--suppressor in lumA--MCF--7 and triple negative--MDA--MB--231 cells, or as an oncogenic factor in HER2+--SKBR3 cells. Mechanistically, fluorescence--resonance energy transfer (FRET)--fluorescence--lifetime imaging microscopy (FLIM) experiments indicated that the effects of 3--OST3A in MCF--7 cells were mediated by altered interactions between HS and fibroblast growth factor--7 (FGF--7). Further, this interplay between HS and FGF--7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3--O--sulfation affects FGFR...

The Pro-Tumoral Activity of Heparan Sulfate 3-O-Sulfotransferase 3B (HS3ST3B) in Breast Cancer MDA-MB-231 Cells Is Dependent on the Expression of Neuropilin-1

“…Hyper-methylation of the genes encoding HS3ST2 and HS3ST3A was described in a number of cancer cells. Reversing methylation restored the expression of theses isozymes and resulted in the suppression of tumor cell growth, suggesting anti-oncogenic properties [ 15 , 16 , 17 , 18 ]. Conversely, we and others demonstrated that forced expression of HS3ST2 resulted in increased proliferation and viability of MDA-MB-231 cells [ 19 , 23 ].…”

“…It is also worth noting that conflicting literature reported that certain HS3STs may act as either anti-oncogenic or tumor-promoting regulators. On the one hand, aberrant methylation of the genes encoding HS3ST2 and HS3ST3A was described in various cancers and tumor cells, and reversing methylation restored their expression and resulted in the suppression of tumor cell growth [ 15 , 16 , 17 , 18 ]. On the other hand, HS3ST2, 3B and 4 were reported to promote cancer progression.…”

The exostosin family of glycosyltransferases: mRNA expression profiles and heparan sulphate structure in human breast carcinoma cell lines

“…Recently, EXT1 was found to be elevated in plasma of human cholangiocarcinoma patients and proposed to be the prognostic marker for cholangiocarcinoma [52]. Genetic loss of NDST4 in colorectal cancer [53] and high HS 3-O-sulphotransferase 3A expression in HER2-positive breast cancer patients [11] were shown to be associated with poor prognosis. Other studies have investigated how changes in HS biosynthetic enzyme expression levels influence growth factor responses in breast cancer.…”

Sulfotransferase and Heparanase: Remodeling Engines in Promoting Virus Infection and Disease Development

“…Similarly, Filoviruses, including Ebola virus (EBOV) and Marburg virus (MARV), known to cause hemorrhagic fever with a high mortality rate are also known to use cell surface HS and enzyme EXT-1 involved in HS-biosynthesis (Riblett et al, 2016 ). In addition, Rift Valley fever virus (RVFV), also an emerging pathogen that can cause lethal hemorrhagic fever syndrome in humans, has been documented to use HS during the initial stages of infection (Mao et al, 2016 ).…”