WWOX, the chromosomal fragile site FRA16D spanning gene: its role in metabolism and contribution to cancer

Abstract

The WWOX gene spans the common chromosomal fragile site FRA16D that is located within a massive (780 kb) intron. The WWOX gene is very long, at 1.1 Mb, which may contribute to the very low abundance of the full-length 1.4 kb mRNA. Alternative splicing also accounts for a variety of aberrant transcripts, most of which are devoid of C-terminal sequences required for WWOX to act as an oxidoreductase. The mouse WWOX gene also spans a chromosomal fragile site implying some sort of functional relationship that confers a selective advantage. The encoded protein domains of WWOX are conserved through evolution (between humans and Drosophila melanogaster) and include WW domains, an NAD -binding site, short-chain dehydrogenase/reductase enzyme and nuclear compartmentalization signals. This homology has enabled functional analyses in D. melanogaster that demonstrate roles for WWOX in reactive oxygen species regulation and metabolism. Indeed the human WWOX gene is also responsive to altered metabolism. Cancer cells typically exhibit altered metabolism (Warburg effect). Many cancers exhibit FRA16D DNA instability that results in aberrant WWOX expression and is associated with poor prognosis for these cancers. It is therefore thought that aberrant WWOX expression contributes to the altered metabolism in cancer. In addition, others have found that a specific (low-expression) allele of WWOX genotype contributes to cancer predisposition.

Keywords: Chromosomal fragile site; FRA16D; altered metabolism; oxidoreductase.

Figure 1

Summary box 1 – common chromosomal fragile sites and their genes.

Figure 2

Summary box 2 – WWOX in cancer initiation and progression

Figure 3

Phylogenetic tree of WWOX orthologs from various species and other oxidoreductases in Drosophila melanogaster. Distinct sequence relationships through evolution of WWOX orthologs in various species are evident when compared to other oxidoreductases (in this case from Drosophila). Note: all species have a single WWOX ortholog except Caenorhabditis elegans with two, neither of which has WW domains. Figure modified from that of O’Keefe et al.

Figure 4

Homology between orthologs WWOX protein sequences. Alignment of WWOX protein sequences from human, chicken, Drosophila melanogaster, zebrafish, and mouse. Majority sequence is indicated with color coding for identity between 6, 5, 4, 3, and 2 sequences. The two WW domains are indicated by blue shading. Sequences comprising the SDR enzyme are indicated by red shading, and the putative “WWOX substrate binding site” is shaded in green. (A color version of this figure is available in the online journal.)