Sirs
After conducting a census of 291 proven human cancer genes and classifying them according to function, Futreal et al. observed that the most prevalent and most significantly over-represented domain encoded by these cancer genes is the protein kinase domain. Their study — which used the human proteome extracted from SwissProt/TrEMBL databases — reported that 27 out of 643 known protein kinases were represented in the census, whereas only 6.3 would be predicted to be included by chance1. However, we were surprised to find no mention of ubiquitylation-related genes in this census. Sun and Chen recently discussed the respective roles of the ubiquitylation and phosphorylation mechanisms in cell signalling2. Notably, they pointed to the apparently similar overall numbers of ubiquitylation- and phosphorylation-related enzymes encoded by the human genome and suggested that the regulatory functions of protein ubiquitylation could be as diverse as those of phosphorylation.
To assess the putative contribution of defects in ubiquitylation to tumorigenesis, we first re-examined the human sequence databases to compile an inventory of all ubiquitylation-related genes. Screening of ENSEMBL3, a less redundant database than SwissProt/TrEMBL, yielded 409 genes that encode putative domain-based4 E3 ubiquitin ligase proteins (E3Ps) (Table 1) Given the controversial nature of this domain-based definition, we applied the more stringent annotation-based criterion, retrieving 71 asserted E3Ps (Table 1). Of these, respectively, 15 (out of 409) and 4 (out of 71) are among the 277 cancer genes identified by Futreal et al.1 that are present in ENSEMBL. If E3Ps were to be as closely associated to oncogenesis as protein kinases, 21.8 (or 3.8) of the cancer genes would have been expected to encode domain-based (or annotation-based) E3Ps, whereas only 5.1 (or 0.9) would encode E3Ps if these proteins were not involved in cancer. This over-representation of E3P encoding genes, relative to the null hypothesis, is statistically significant (P-value of Fisher exact test — 0.02% or 1.2% considering, respectively, the 409 or 71 asserted E3Ps), meaning that E3Ps are indeed cancer genes. Some E3Ps that are known to be involved in tumorigenesis, such as PHF9 and MDM2, were also missing from the census of Futreal et al.5,6. Whether distinct E3 ubiquitin ligase domains are associated with specific tumour types remains to be investigated.
At least three of the four asserted cancer-associated E3Ps can function as signal-transduction modulators, including CBL, VHL and BRCA1. Although CBL is a regulator of tyrosine kinase activity7,8, VHL functions as a mediator of the hypoxic response9,10, and the adaptor protein BRCA1, like PHF9, is involved in regulating DNA repair7,5. BRCA1 has also been shown to harbour a phosphopeptide-binding BRCT domain5,11. By contrast, HEI10 has been proposed to function as a cell-cycle regulator12.
To what extent are other members of the ubiquitin pathway associated with cancer? A count of the human genes that encode E2 ubiquitin-conjugating enzymes or ubiquitin proteases yielded 45 and 85 distinct entries, respectively (Table 1), but only one of these was among the cancer genes reported by Futreal et al. indicating that these genes are not associated with cancer. Functional redundancy might explain the low representation of these classes of proteins among the cancer genes listed by Futreal and colleagues. It is interesting to note that the only deubiquitinase present in this list, CYLD, is also involved in signal transduction13,14,15.
Our analyses, based on a relaxed or conservative definition of putative or asserted E3Ps, respectively, indicate that a similar number of E3Ps (17) and protein kinases (27) are involved in cancer formation, together encompassing 15% (44 — 17 from this analysis and the 27 kinases identified by Futreal et al.1) of the 291 cancer genes identified in the census by Futreal et al.1 Further experiments are required to clarify the exact mechanisms by which (de)ubiquitylation contributes to tumorigenesis and the relative contributions of ubiquitylation and phosphorylation to tumour formation, and to determine which distinct domains of ubiquitylation and deubiquitylation enzymes are relevant to cancer.
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Acknowledgements
M.D. is supported by the National Center of Competence in Research Molecular Oncology, a research programme of the Swiss National Science Foundation.
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Beckmann, J., Maurer, F., Delorenzi, M. et al. Ubiquitin ligases as cancer genes. Nat Rev Cancer 4, 654 (2004). https://doi.org/10.1038/nrc1299-c1
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DOI: https://doi.org/10.1038/nrc1299-c1
