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Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

Abstract

Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steady-state Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.

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References

  • Achcar RD, Nikiforova MN, Dacic S, Nicholson AG, Yousem SA . (2009). Mammalian mastermind like 2 11q21 gene rearrangement in bronchopulmonary mucoepidermoid carcinoma. Hum Pathol 40: 854–860.

    Article  CAS  Google Scholar 

  • Behboudi A, Winnes M, Gorunova L, van den Oord JJ, Mertens F, Enlund F et al. (2005). Clear cell hidradenoma of the skin-a third tumor type with a t(11;19)—associated TORC1-MAML2 gene fusion. Genes Chromosomes Cancer 43: 202–205.

    Article  CAS  PubMed  Google Scholar 

  • Bittinger MA, McWhinnie E, Meltzer J, Iourgenko V, Latario B, Liu X et al. (2004). Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins. Curr Biol 14: 2156–2161.

    Article  CAS  PubMed  Google Scholar 

  • Camelo-Piragua SI, Habib C, Kanumuri P, Lago CE, Mason HS, Otis CN . (2009). Mucoepidermoid carcinoma of the breast shares cytogenetic abnormality with mucoepidermoid carcinoma of the salivary gland: a case report with molecular analysis and review of the literature. Hum Pathol 40: 887–892.

    Article  PubMed  Google Scholar 

  • Carling D . (2006). LKB1: a sweet side to Peutz-Jeghers syndrome? Trends Mol Med 12: 144–147.

    Article  CAS  PubMed  Google Scholar 

  • Cheng H, Liu P, Wang ZC, Zou L, Santiago S, Garbitt V et al. (2009). SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal 2: ra35.

    PubMed  PubMed Central  Google Scholar 

  • Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB et al. (2003). TORCs: transducers of regulated CREB activity. Mol Cell 12: 413–423.

    Article  CAS  PubMed  Google Scholar 

  • Coxon A, Rozenblum E, Park YS, Joshi N, Tsurutani J, Dennis PA et al. (2005). Mect1-Maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes. Cancer Res 65: 7137–7144.

    Article  CAS  PubMed  Google Scholar 

  • Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J et al. (2007). Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366–369.

    Article  CAS  PubMed  Google Scholar 

  • Enlund F, Behboudi A, Andren Y, Oberg C, Lendahl U, Mark J et al. (2004). Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res 292: 21–28.

    Article  CAS  PubMed  Google Scholar 

  • Fu A, Screaton RA . (2008). Using kinomics to delineate signaling pathways: control of CRTC2/TORC2 by the AMPK family. Cell Cycle 7: 3823–3828.

    Article  CAS  PubMed  Google Scholar 

  • Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP et al. (2003). Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2: 28.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hezel AF, Bardeesy N . (2008). LKB1; linking cell structure and tumor suppression. Oncogene 27: 6908–6919.

    Article  CAS  PubMed  Google Scholar 

  • Holla VR, Mann JR, Shi Q, DuBois RN . (2006). Prostaglandin E2 regulates the nuclear receptor NR4A2 in colorectal cancer. J Biol Chem 281: 2676–2682.

    Article  CAS  PubMed  Google Scholar 

  • Hong SP, Leiper FC, Woods A, Carling D, Carlson M . (2003). Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 100: 8839–8843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL et al. (2008). Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412: 211–221.

    Article  CAS  PubMed  Google Scholar 

  • Iourgenko V, Zhang W, Mickanin C, Daly I, Jiang C, Hexham JM et al. (2003). Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc Natl Acad Sci USA 100: 12147–12152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P et al. (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature 448: 807–810.

    Article  CAS  PubMed  Google Scholar 

  • Katajisto P, Vallenius T, Vaahtomeri K, Ekman N, Udd L, Tiainen M et al. (2007). The LKB1 tumor suppressor kinase in human disease. Biochim Biophys Acta 1775: 63–75.

    CAS  PubMed  Google Scholar 

  • Katoh Y, Takemori H, Lin XZ, Tamura M, Muraoka M, Satoh T et al. (2006). Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade. FEBS J 273: 2730–2748.

    Article  CAS  PubMed  Google Scholar 

  • Kaye FJ . (2006). Emerging biology of malignant salivary gland tumors offers new insights into the classification and treatment of mucoepidermoid cancer. Clin Cancer Res 12: 3878–3881.

    Article  PubMed  Google Scholar 

  • Kaye FJ . (2009). Mutation-associated fusion cancer genes in solid tumors. Mol Cancer Ther 8: 1399–1408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kazakov DV, Vanecek T, Belousova IE, Mukensnabl P, Kollertova D, Michal M . (2007). Skin-type hidradenoma of the breast parenchyma with t(11;19) translocation: hidradenoma of the breast. Am J Dermatopathol 29: 457–461.

    Article  PubMed  Google Scholar 

  • Ke N, Claassen G, Yu DH, Albers A, Fan W, Tan P et al. (2004). Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer Res 64: 8208–8212.

    Article  CAS  PubMed  Google Scholar 

  • Komiya T, Park Y, Modi S, Coxon A, Oh H, Kaye FJ . (2006). Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation. Oncogene 25: 6128–6132.

    Article  CAS  PubMed  Google Scholar 

  • Kovacs KA, Steullet P, Steinmann M, Do KQ, Magistretti PJ, Halfon O et al. (2007). TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity. Proc Natl Acad Sci USA 104: 4700–4705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lennerz JK, Perry A, Mills JC, Huettner PC, Pfeifer JD . (2009). Mucoepidermoid Carcinoma of the Cervix: Another Tumor With the t(11;19)-associated CRTC1-MAML2 Gene Fusion. Am J Surg Pathol 33: 835–43.

    Article  PubMed  Google Scholar 

  • Li QX, Ke N, Sundaram R, Wong-Staal F . (2006). NR4A1, 2, 3—an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Histol Histopathol 21: 533–540.

    CAS  PubMed  Google Scholar 

  • Li S, Zhang C, Takemori H, Zhou Y, Xiong ZQ . (2009). TORC1 regulates activity-dependent CREB-target gene transcription and dendritic growth of developing cortical neurons. J Neurosci 29: 2334–2343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Tai HH . (2009). Activation of Thromboxane A2 Receptors Induces Orphan Nuclear Receptor Nurr1 Expression and Stimulates Cell Proliferation in Human Lung Cancer Cells. Carcinogenesis 30: 1606–1613.

    Article  PubMed  Google Scholar 

  • Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J et al. (2004). LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23: 833–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS . (2002). Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16: 948–958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P . (2006). NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat Med 12: 1048–1055.

    Article  CAS  PubMed  Google Scholar 

  • Ravnskjaer K, Kester H, Liu Y, Zhang X, Lee D, Yates 3rd JR et al. (2007). Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression. EMBO J 26: 2880–2889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez-Cespedes M . (2007). A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 26: 7825–7832.

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM et al. (2002). Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 62: 3659–3662.

    CAS  PubMed  Google Scholar 

  • Screaton RA, Conkright MD, Katoh Y, Best JL, Canettieri G, Jeffries S et al. (2004). The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119: 61–74.

    Article  CAS  PubMed  Google Scholar 

  • Shah U, Sharpless NE, Hayes DN . (2008). LKB1 and lung cancer: more than the usual suspects. Cancer Res 68: 3562–3565.

    Article  CAS  PubMed  Google Scholar 

  • Shaw RJ . (2009). Tumor suppression by LKB1: SIK-ness prevents metastasis. Sci Signal 2: pe55.

    Article  PubMed  Google Scholar 

  • Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA et al. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6: 91–99.

    Article  CAS  PubMed  Google Scholar 

  • Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA et al. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiainen M, Ylikorkala A, Makela TP . (1999). Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Proc Natl Acad Sci USA 96: 9248–9251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tirado Y, Williams MD, Hanna EY, Kaye FJ, Batsakis JG, El-Naggar AK . (2007). CRTC1/MAML2 fusion transcript in high grade mucoepidermoid carcinomas of salivary and thyroid glands and Warthin's tumors: implications for histogenesis and biologic behavior. Genes Chromosomes Cancer 46: 708–715.

    Article  CAS  PubMed  Google Scholar 

  • Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T et al. (2003). t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33: 208–213.

    Article  CAS  PubMed  Google Scholar 

  • Wallen-Mackenzie A, Mata de Urquiza A, Petersson S, Rodriguez FJ, Friling S, Wagner J et al. (2003). Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes Dev 17: 3036–3047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Goode J, Best J, Meltzer J, Schilman PE, Chen J et al. (2008). The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila. Cell Metab 7: 434–444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H et al. (2005). Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. EMBO J 24: 2391–2402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Wu H, Li S, Chen Q, Cheng XW, Zheng J et al. (2006). Requirement of TORC1 for late-phase long-term potentiation in the hippocampus. PLoS ONE 1: e16.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Jie Li (NINDS) for brain tumor samples. We are grateful to William Meyerson for technical assistance.

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Correspondence to F J Kaye.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Komiya, T., Coxon, A., Park, Y. et al. Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer. Oncogene 29, 1672–1680 (2010). https://doi.org/10.1038/onc.2009.453

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