Senescence Escape in Melanoma: Role of Spleen Tyrosine Kinase SYK
Tissue homeostasis is maintained by appropriate innate cellular responses to various oncogenic or genotoxic stresses. Flaws in pathways controlling these responses can cause cancer. Cellular senescence is a critical tumor suppressor mechanism and a well-recognized failsafe program against melanoma progression. Melanoma is a lethal skin cancer of increasing incidence that is linked to solar ultraviolet (UV) radiation and oncogenic events such as activating mutations in BRAF. Understanding why senescence fails to constraint malignant transformation of epidermal melanocytes is a key question in melanoma biology. Spleen tyrosine kinase (Syk) is a multifunction protein tyrosine kinase critical for immune and hematopoietic signaling that has been implicated in tumor suppression of several carcinomas and skin melanomas. Our recent report indicated that Syk exerts its melanoma suppressive function by inducing p53-dependent premature senescence and stress-activated c-Jun N-terminal kinases (JNKs) activation. We proposed that epigenetic inactivation of Syk that is generally observed in primary and metastatic melanoma cells may contribute to senescence escape and tumorigenicity. In this chapter, we discuss this new aspect of Syk function in melanomagenesis with a focus on cellular circuits controlling BRAFV600E-induced senescence. We also examine the potential implication of Syk in p53-mediated UVB stress signaling in melanocytes.
Keywordsc-Jun N-terminal kinases (JNK) activation Environmental stress Genetic disruption of p53 pathway Immunoreceptor tyrosine-based activation motifs (ITAMs) KIT, ERBB4 and CDK4 genes MDM2 activity and PTEN expression Melanocyte transformation Pathogenesis of melanoma Secreted protein acidic and rich in cysteine (SPARC) Syk in melanomagenesis
This work was supported by INSERM and research grants from the ARC foundation.
- Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, Myers EE, Huang B, Jackson DG, Ferrari VA, Tybulewicz V, Lowell CA, Lepore JJ, Koretzky GA, Kahn ML (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299:247–251PubMedCrossRefGoogle Scholar
- Bailet O, Fenouille N, Abbe P, Robert G, Rocchi S, Gonthier N, Denoyelle C, Ticchioni M, Ortonne JP, Ballotti R, Deckert M, Tartare-Deckert S (2009) Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest. Cancer Res 69:2748–2756PubMedCrossRefGoogle Scholar
- Baudot AD, Jeandel PY, Mouska X, Maurer U, Tartare-Deckert S, Raynaud SD, Cassuto JP, Ticchioni M, Deckert M (2009) The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCdelta and proteasome-dependent regulation of Mcl-1 expression. Oncogene 28:3261–3273PubMedCrossRefGoogle Scholar
- de Keizer PL, Packer LM, Szypowska AA, Riedl-Polderman PE, van den Broek NJ, de Bruin A, Dansen TB, Marais R, Brenkman AB, Burgering BM (2010) Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence. Cancer Res 70:8526–8536PubMedCrossRefGoogle Scholar
- Delmas V, Beermann F, Martinozzi S, Carreira S, Ackermann J, Kumasaka M, Denat L, Goodall J, Luciani F, Viros A, Demirkan N, Bastian BC, Goding CR, Larue L (2007) Beta-catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development. Genes Dev 21:2923–2935PubMedCrossRefGoogle Scholar
- Fenouille N, Puissant A, Tichet M, Zimniak G, Abbe P, Mallavialle A, Rocchi S, Ortonne JP, Deckert M, Ballotti R, Tartare-Deckert S (2011a) SPARC functions as an anti-stress factor by inactivating p53 through Akt-mediated MDM2 phosphorylation to promote melanoma cell survival. Oncogene 30:4887–4900PubMedCrossRefGoogle Scholar
- Finney BA, Schweighoffer E, Navarro-Nunez L, Benezech C, Barone F, Hughes CE, Langan SA, Lowe KL, Pollitt AY, Mourao-Sa D, Sheardown S, Nash GB, Smithers N, Reis e Sousa C, Tybulewicz VL, Watson SP (2012) CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development. Blood 119:1747–1756PubMedCrossRefGoogle Scholar
- Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA (2009) Inhibition of Syk with fostamatinib disodium has significant clinical activity in non Hodgkin’s lymphoma and chronic lymphocytic leukemia. Blood 115:2578–2585PubMedCrossRefGoogle Scholar
- Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC (2012) MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 18:1239–1247PubMedCrossRefGoogle Scholar
- Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA (2012) A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481:329–334PubMedGoogle Scholar