The Collagen Prolyl Hydroxylases Are Novel Transcriptionally Silenced Genes in Lymphoma

Br J Cancer. 2012 Oct 9;107(8):1423-32. doi: 10.1038/bjc.2012.380. Epub 2012 Sep 6.

Abstract

Background: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http://www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant β subunit encoded by P4HB.

Methods: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow.

Results: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma.

Conclusions: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Collagen / genetics*
  • Collagen / metabolism
  • CpG Islands / genetics
  • Gene Expression Regulation
  • Gene Silencing
  • Humans
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Methylation
  • Procollagen-Proline Dioxygenase / genetics*
  • Procollagen-Proline Dioxygenase / metabolism

Substances

  • Collagen
  • Procollagen-Proline Dioxygenase