PMID- 29955035
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2157-9024 (Print)
IS  - 2157-9024 (Electronic)
IS  - 2157-9024 (Linking)
VI  - 7
IP  - 6
DP  - 2018 Jun 29
TI  - Identification of strong intron enhancer in the heparanase gene: effect of 
      functional rs4693608 variant on HPSE enhancer activity in hematological and solid 
      malignancies.
PG  - 51
LID - 10.1038/s41389-018-0060-8 [doi]
LID - 51
AB  - Heparanase is an endo-beta-glucuronidase that specifically cleaves the saccharide 
      chains of heparan sulfate (HS) proteoglycans and releases HS-bound cytokines, 
      chemokines, and bioactive growth-promoting factors. Heparanase plays an important 
      role in the nucleus as part of an active chromatin complex. Our previous studies 
      revealed that rs4693608 correlates with heparanase levels and increased risk of 
      acute and extensive chronic graft vs. host disease (GVHD). Discrepancy between 
      recipient and donor in this SNP significantly affected the risk of acute GVHD. In 
      the present study, we analyzed the HPSE gene region, including rs4693608, and 
      demonstrated that this region exhibits SNPs-dependent enhancer activity. Analysis 
      of nuclear proteins from normal leukocytes revealed their binding to DNA probe of 
      both alleles with higher affinity to allele G. All malignant cell lines and 
      leukemia samples disclosed a shift of the main bands in comparison to normal 
      leukocytes. At least five additional shifted bands were bound to allele A while 
      allele G probe was bound to only one main DNA/protein complex. Additional SNPs 
      rs4693083, rs4693084, and rs4693609 were found in strong linkage disequilibrium 
      (LD) with rs11099592 (exon 7). Only rs4693084 affected protein binding to DNA in 
      cell lines and leukemia samples. As a result of the short distance between 
      rs4693608 and rs4693084, both SNPs may be included in a common DNA/protein 
      complex. DNA pull-down assay revealed that heparanase is involved in 
      self-regulation by negative feedback in rs4693608-dependent manner. During 
      carcinogenesis, heparanase self-regulation is discontinued and the helicase-like 
      transcription factor begins to regulate this enhancer region. Altogether, our 
      study elucidates conceivable mechanism(s) by which rs4693608 SNP regulates HPSE 
      gene expression and the associated disease outcome.
FAU - Ostrovsky, Olga
AU  - Ostrovsky O
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel. olga.ostrovsky@sheba.health.gov.il.
FAU - Grushchenko-Polaq, Ania Hava
AU  - Grushchenko-Polaq AH
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
FAU - Beider, Katia
AU  - Beider K
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
FAU - Mayorov, Margarita
AU  - Mayorov M
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
FAU - Canaani, Jonathan
AU  - Canaani J
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
FAU - Shimoni, Avichai
AU  - Shimoni A
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
FAU - Vlodavsky, Israel
AU  - Vlodavsky I
AD  - Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, 
      Technion, Haifa, Israel.
FAU - Nagler, Arnon
AU  - Nagler A
AD  - Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical 
      Center, Tel-Hashomer, Israel.
LA  - eng
PT  - Journal Article
DEP - 20180629
PL  - United States
TA  - Oncogenesis
JT  - Oncogenesis
JID - 101580004
PMC - PMC6023935
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/06/30 06:00
MHDA- 2018/06/30 06:01
PMCR- 2018/06/29
CRDT- 2018/06/30 06:00
PHST- 2017/09/05 00:00 [received]
PHST- 2018/05/20 00:00 [accepted]
PHST- 2018/05/03 00:00 [revised]
PHST- 2018/06/30 06:00 [entrez]
PHST- 2018/06/30 06:00 [pubmed]
PHST- 2018/06/30 06:01 [medline]
PHST- 2018/06/29 00:00 [pmc-release]
AID - 10.1038/s41389-018-0060-8 [pii]
AID - 60 [pii]
AID - 10.1038/s41389-018-0060-8 [doi]
PST - epublish
SO  - Oncogenesis. 2018 Jun 29;7(6):51. doi: 10.1038/s41389-018-0060-8.