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Front Oncol. 2014 Apr 15;4:79. doi: 10.3389/fonc.2014.00079. eCollection 2014.

Transcriptional Activity of Heparan Sulfate Biosynthetic Machinery is Specifically Impaired in Benign Prostate Hyperplasia and Prostate Cancer.

Frontiers in oncology

Anastasia V Suhovskih, Alexandra Y Tsidulko, Olesya S Kutsenko, Anna V Kovner, Svetlana V Aidagulova, Ingemar Ernberg, Elvira V Grigorieva

Affiliations

  1. Institute of Molecular Biology and Biophysics SD RAMS , Novosibirsk , Russia ; Novosibirsk State University , Novosibirsk , Russia.
  2. Institute of Molecular Biology and Biophysics SD RAMS , Novosibirsk , Russia.
  3. Research Center of Clinical and Experimental Medicine SD RAMS , Novosibirsk , Russia.
  4. Novosibirsk State Medical University , Novosibirsk , Russia.
  5. MTC, Karolinska Institute , Stockholm , Sweden.
  6. Institute of Molecular Biology and Biophysics SD RAMS , Novosibirsk , Russia ; MTC, Karolinska Institute , Stockholm , Sweden.

PMID: 24782989 PMCID: PMC3995048 DOI: 10.3389/fonc.2014.00079

Abstract

Heparan sulfates (HSs) are key components of mammalian cells surface and extracellular matrix. Structure and composition of HS, generated by HS-biosynthetic system through non-template-driven process, are significantly altered in cancer tissues. The aim of this study was to investigate the involvement of HS-metabolic machinery in prostate carcinogenesis. Transcriptional patterns of HS-metabolic enzymes (EXT1, EXT2, NDST1, NDST2, GLCE, 3OST1/HS3ST1, SULF1, SULF2, HPSE) were determined in normal, benign, and cancer human prostate tissues and cell lines (PNT2, LNCaP, PC3, DU145). Stability of the HS-metabolic system patterns under the pressure of external or internal stimuli was studied. Overall impairment of transcriptional activity of HS-metabolic machinery was detected in benign prostate hyperplasia, while both significant decrease in the transcriptional activity and changes in the expression patterns of HS metabolism-involved genes were observed in prostate tumors. Prostate cancer cell lines possessed specific transcriptional patterns of HS metabolism-involved genes; however, expression activity of the system was similar to that of normal prostate PNT2 cells. HS-metabolic system was able to dynamically react to different external or internal stimuli in a cell type-dependent manner. LNCaP cells were sensitive to the external stimuli (5-aza-deoxycytidin or Trichostatin A treatments; co-cultivation with human fibroblasts), whereas PC3 cells almost did not respond to the treatments. Ectopic GLCE over-expression resulted in transcriptional activation of HS-biosynthetic machinery in both cell lines, suggesting an existence of a self-regulating mechanism for the coordinated transcription of HS metabolism-involved genes. Taken together, these findings demonstrate impairment of HS-metabolic system in prostate tumors in vivo but not in prostate cancer cells in vitro, and suggest that as a potential microenvironmental biomarker for prostate cancer diagnostics and treatment.

Keywords: biosynthesis; expression; heparan sulfate; prostate cancer; proteoglycan; transcriptional pattern

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