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Logo of jbcThe Journal of Biological Chemistry
 
J Biol Chem. 2012 October 12; 287(42): 35442.
PMCID: PMC3471730

Targeting YAP Acetylation in Cancer

Nishina and colleagues (1) provided important evidence that suggested the implication of the Hippo pathway in methyl methanesulfonate (MMS)-induced DNA damage. The work looks impressive. However, contribution of factors other than Yes-associated protein (YAP) cannot be ruled out. YAP is a nuclear effector that binds to the TEA domain (TEAD) transcription factor and could promote nuclear/cytoplasmic translocation as well as its paralog TAZ (transcriptional coactivator with PDZ-binding motif) (2). TAZ is an important transcriptional coactivator sharing significant homology with YAP (3) and plays an important role in cancer (4). Therefore, other factors such as TAZ could contribute to this action.

YAP is a candidate oncogene amplified in many human cancers (5). In this study, it seemed that the YAP acetylation cycle is an important defensive mechanism for DNA damage. The authors proposed that hYAP acetylation could improve the sensitivity of HeLa cells to chemotherapy (Fig. 7A in Ref. 1). Generalization, however, is dangerous due to the limited number of cancer cell lines and the reliance on in vitro assays. Future studies in tumor-bearing animal subjects are needed to confirm the findings.

Furthermore, YAP is highly expressed in cancer cells as well as in certain normal tissues, such as the lungs, prostate, and ovary. Post-translational modification of YAP, such as acetylation, may have differential effects on the responses of cancer versus normal cells to chemo/radiotherapy. Specifically, the YAP acetylation cycle is a balance between acetylation and deacetylation and is subjected to regulation by the transcriptional coactivator activity of hYAP (Fig. 7B in Ref. 1). Thus, targeting YAP by acetylation may be favorable for cancer treatment but unfavorable for normal tissue repair. The nonspecific toxicities or adverse effects were not mentioned in this study and need to be examined in the future.

References

1. Hata S., Hirayama J., Kajiho H., Nakagawa K., Hata Y., Katada T., Furutani-Seiki M., Nishina H. (2012) Novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to Sn2 alkylating agents. J. Biol. Chem. 287, 22089–22098 [PMC free article] [PubMed]
2. Dupont S., Morsut L., Aragona M., Enzo E., Giulitti S., Cordenonsi M., Zanconato F., Le Digabel J., Forcato M., Bicciato S., Elvassore N., Piccolo S. (2011) Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 [PubMed]
3. Hong W., Guan K. L. (2012) The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin. Cell Dev. Biol. 10.1016/j.semcdb.2012.05.004 [PMC free article] [PubMed] [Cross Ref]
4. Skinner M. (2012) Cancer stem cells: TAZ takes centre stage. Nat. Rev. Cancer 12, 82–83 [PubMed]
5. Stanger B. Z. (2012) Quit your YAPing: a new target for cancer therapy. Genes Dev. 26, 1263–1267 [PubMed]

Articles from The Journal of Biological Chemistry are provided here courtesy of American Society for Biochemistry and Molecular Biology