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Rho GTPases in cancer: friend or foe?

Oncogene volume 38, pages 7447–7456 (2019)Cite this article

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Abstract

The Rho GTPases RhoA, Rac1, and Cdc42 are important regulators of cytoskeletal dynamics. Although many in vitro and in vivo data indicate tumor-promoting effects of activated Rho GTPases, also tumor suppressive functions have been described, suggesting either highly cell-type-specific functions for Rho GTPases in cancer or insufficient cancer models. The availability of a large number of cancer genome-sequencing data by The Cancer Genome Atlas (TCGA) allows for the investigation of Rho GTPase function in human cancers in silico. This information should be used to improve our in vitro and in vivo cancer models, which are essential for a molecular understanding of Rho GTPase function in malignant tumors and for the potential development of cancer drugs targeting Rho GTPase signaling.

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References

  1. Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol. 2005;21:247–69.

    CAS  PubMed  Google Scholar 

  2. Bustelo XR, Sauzeau V, Berenjeno IM. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 2007;29:356–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pedersen E, Brakebusch C. Rho GTPase function in development: how in vivo models change our view. Exp Cell Res. 2012;318:1779–87.

    CAS  PubMed  Google Scholar 

  4. Aspenström P. Fast-cycling Rho GTPases. Small GTPases. 2018;29:1–8.

    Google Scholar 

  5. Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol. 2016;17:496–510.

    CAS  PubMed  Google Scholar 

  6. Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005;6:167–80.

    CAS  PubMed  Google Scholar 

  7. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.

    CAS  PubMed  Google Scholar 

  8. Garcia-Mata R, Boulter E, Burridge K. The ‘invisible hand’: regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol. 2011;12:493–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Peck J, Douglas G 4th, Wu CH, Burbelo PD. Human RhoGAP domain-containing proteins: structure, function and evolutionary relationships. FEBS Lett. 2002;528:27–34.

    CAS  PubMed  Google Scholar 

  10. Li H, Peyrollier K, Kilic G, Brakebusch C. Rho GTPases and cancer. Biofactors. 2014;40:226–35.

    CAS  PubMed  Google Scholar 

  11. Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018;217:447–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Prendergast GC, Khosravi-Far R, Solski PA, Kurzawa H, Lebowitz PF, Der CJ. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995;10:2289–96.

    CAS  PubMed  Google Scholar 

  13. Lin R, Bagrodia S, Cerione R, Manor D. A novel Cdc42Hs mutant induces cellular transformation. Curr Biol. 1997;7:794–7.

    CAS  PubMed  Google Scholar 

  14. Karlsson R, Pedersen ED, Wang Z, Brakebusch C. Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 2009;1796:91–8.

    CAS  PubMed  Google Scholar 

  15. Porter AP, Papaioannou A, Malliri A. Deregulation of Rho GTPases in cancer. Small GTPases. 2016;7:123–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kazanietz MG, Caloca MJ. The Rac GTPase in cancer: from old concepts to new paradigms. Cancer Res. 2017;77:5445–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cardama GA, Gonzalez N, Maggio J, Menna PL, Gomez DE. Rho GTPases as therapeutic targets in cancer. Int J Oncol. 2017;51:1025–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zandvakili I, Lin Y, Morris JC, Zheng Y. Rho GTPases: anti- or pro-neoplastic targets? Oncogene. 2017;36:3213–22.

    CAS  PubMed  Google Scholar 

  19. Bustelo XR. RHO GTPases in cancer: known facts, open questions, and therapeutic challenges. Biochem Soc Trans. 2018;46:741–60.

    CAS  PubMed  Google Scholar 

  20. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.

    Google Scholar 

  21. Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE, et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell. 2017;32:701–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zandvakili I, Davis AK, Hu G, Zheng Y. Loss of RhoA exacerbates, rather than dampens, oncogenic K-Ras induced lung adenoma formation in mice. PLoS ONE. 2015;10:e0127923.

    PubMed  PubMed Central  Google Scholar 

  23. Ridley AJ. RhoA, RhoB and RhoC have different roles in cancer cell migration. J Microsc. 2013;251:242–9.

    CAS  PubMed  Google Scholar 

  24. Vennin C, Rath N, Pajic M, Olson MF, Timpson P. Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy. Small GTPases. 2017;3:1–8.

    Google Scholar 

  25. García-Mariscal A, Li H, Pedersen E, Peyrollier K, Ryan KM, Stanley A, et al. Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. Oncogene. 2018;37:847–60.

    PubMed  Google Scholar 

  26. Vega FM, Ridley AJ. The RhoB small GTPase in physiology and disease. Small GTPases. 2018;9:384–93.

    CAS  PubMed  Google Scholar 

  27. Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014;6:583–7.

    Google Scholar 

  28. Cancer Genome Atlas Research N. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9.

    Google Scholar 

  29. Nishizawa T, Nakano K, Harada A, Kakiuchi M, Funahashi SI, Suzuki M, et al. DGC-specific RHOA mutations maintained cancer cell survival and promoted cell migration via ROCK inactivation. Oncotarget 2018;9:23198–207.

    PubMed  PubMed Central  Google Scholar 

  30. Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med. 1999;5:221–5.

    CAS  PubMed  Google Scholar 

  31. Rodrigues P, Macaya I, Bazzocco S, Mazzolini R, Andretta E, Dopeso H, et al. RHOA inactivation enhances Wnt signalling and promotes colorectal cancer. Nat Commun. 2014;5:5458.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Nobis M, Herrmann D, Warren SC, Kadir S, Leung W, Killen M, et al. A RhoA-FRET biosensor mouse for intravital imaging in normal tissue homeostasis and disease contexts. Cell Rep. 2017;21:274–88.

    CAS  PubMed  Google Scholar 

  33. Zuo Y, Ulu A, Chang JT, Frost JA. Contributions of the RhoA guanine nucleotide exchange factor Net1 to polyoma middle T antigen-mediated mammary gland tumorigenesis and metastasis. Breast Cancer Res. 2018;20:41.

    PubMed  PubMed Central  Google Scholar 

  34. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014;505:495–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Humphries B, Wang Z, Li Y, Jhan JR, Jiang Y, Yang C. ARHGAP18 Downregulation by miR-200b suppresses metastasis of triple-negative breast cancer by enhancing activation of RhoA. Cancer Res. 2017;77:4051–64.

    CAS  PubMed  Google Scholar 

  36. Palomero T, Couronné L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:171–5.

    CAS  PubMed  Google Scholar 

  38. Yoo HY, Sung MK, Lee SH, Kim S, Lee H, Park S, et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014;46:371–5.

    CAS  PubMed  Google Scholar 

  39. Cortes JR, Ambesi-Impiombato A, Couronné L, Quinn SA, Kim CS, da Silva Almeida AC, et al. RHOA G17V induces T follicular helper cell specification and promotes lymphomagenesis. Cancer Cell 2018;33:259–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang JQ, Kalim KW, Li Y, Zhang S, Hinge A, Filippi MD, et al. RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J Allergy Clin Immunol. 2016;137:231–45.

    CAS  PubMed  Google Scholar 

  41. Nagata Y, Kontani, Enami T, Kataoka K, Ishii R, Totoki Y, et al. Variegated RHOA mutations in adult T-cell leukemia/lymphoma. Blood 2016;127:596–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rohde M, Richter J, Schlesner M, Betts MJ, Claviez A, Bonn BR, et al. Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols. Genes Chromosomes Cancer 2014;53:911–6.

    CAS  PubMed  Google Scholar 

  43. O’Hayre M, Inoue A, Kufareva I, Wang Z, Mikelis CM, Drummond RA, et al. Inactivating mutations in GNA13 and RHOA in Burkitt’s lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells. Oncogene 2016;35:3771–80.

    PubMed  Google Scholar 

  44. Hakem A, Sanchez-Sweatman O, You-Ten A, Duncan G, Wakeham A, Khokha R, et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev 2005;19:1974–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Ju JA, Gilkes DM. RhoB: team oncogene or team tumor suppressor? Genes (Basel). 2018;9:pii: E67.

    Google Scholar 

  46. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012;44:1006–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tomino T, Tajiri H, Tatsuguchi T, Shirai T, Oisaki K, Matsunaga S, et al. DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation. Biochem Biophys Res Commun. 2018;497:298–304.

    CAS  PubMed  Google Scholar 

  49. Davis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ. RAC1P29S is a spontaneously activating cancer-associated GTPase. Proc Natl Acad Sci USA 2013;110:912–7.

    CAS  PubMed  Google Scholar 

  50. Chang MT, Asthana S, Gao SP, Lee BH, Chapman JS, Kandoth C, et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat Biotechnol. 2016;34:155–63.

    CAS  PubMed  Google Scholar 

  51. Bagrodia A, Lee BH, Lee W, Cha EK, Sfakianos JP, Iyer G, et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J Clin Oncol. 2016;34:4000–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kissil J, Walmsley M, Hanlon L, Haigis K, Bender Kim C, Sweet-Cordero A, et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res. 2007;67:8089–94.

    CAS  PubMed  Google Scholar 

  53. Wang Z, Pedersen E, Basse A, Lefever T, Peyrollier K, Kapoor S, et al. Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek- Erk hyperactivation and hyperproliferation in vivo. Oncogene. 2010;29:3362–73.

    CAS  PubMed  Google Scholar 

  54. Wu CY, Carpenter ES, Takeuchi KK, Halbrook CJ, Peverley LV, Bien H, et al. PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice. Gastroenterology. 2014;147:1405–16.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rane CK, Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–9.

    CAS  PubMed  Google Scholar 

  56. Araiza-Olivera D, Feng Y, Semenova G, Prudnikova TY, Rhodes J, Chernoff J. Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors. Oncogene 2018;37:944–52.

    CAS  PubMed  Google Scholar 

  57. Chauhan BK, Lou M, Zheng Y, Lang RA. Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci USA 2011;108:18289–94.

    CAS  PubMed  Google Scholar 

  58. Roberts PJ, Mitin N, Keller PJ, Chenette EJ, Madigan JP, Currin RO, et al. Rho family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J Biol Chem. 2008;283:25150–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Dubash AD, Guilluy C, Srougi MC, Boulter E, Burridge K, García-Mata R. The small GTPase RhoA localizes to the nucleus and is activated by Net1 and DNA damage signals. PLoS ONE 2011;6:e17380.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Michaelson D, Abidi W, Guardavaccaro D, Zhou M, Ahearn I, Pagano M, et al. Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division. J Cell Biol. 2008;181:485–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Navarro-Lérida I, Pellinen T, Sanchez SA, Guadamillas MC, Wang Y, Mirtti T, et al. Rac1 nucleocytoplasmic shuttling drives nuclear shape changes and tumor invasion. Dev Cell 2015;32:318–34.

    PubMed  Google Scholar 

  62. van Hengel J, D’Hooge P, Hooghe B, Wu X, Libbrecht L, De Vos R, et al. Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver. Gastroenterology 2008;134:781–92.

    PubMed  Google Scholar 

  63. Mizukawa B, O’Brien E, Moreira DC, Wunderlich M, Hochstetler CL, Duan X, et al. The cell polarity determinant CDC42 controls division symmetry to block leukemia cell differentiation. Blood. 2017;130:1336–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Li H, Petersen S, Garcia Mariscal A, Brakebusch C. Negative regulation of p53-induced senescence by N-WASP is crucial for DMBA/TPA-induced skin tumor formation. Cancer Res. 2019;79:2167–81.

    CAS  PubMed  Google Scholar 

  65. Schaefer A, Reinhard NR, Hordijk PL. Toward understanding RhoGTPase specificity: structure, function and local activation. Small GTPases 2014;5:6.

    PubMed  Google Scholar 

  66. Aspenström P, Ruusala A, Pacholsky D. Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp Cell Res. 2007;313:3673–9.

    PubMed  Google Scholar 

  67. Roberts PJ, Mitin N, Keller PJ, Chenette EJ, Madigan JP, Currin RO, et al. Rho Family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J Biol Chem. 2008;283:25150–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347(Jan):1260419.

    PubMed  Google Scholar 

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  1. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark

    Julius H. Svensmark & Cord Brakebusch

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Svensmark, J.H., Brakebusch, C. Rho GTPases in cancer: friend or foe?. Oncogene 38, 7447–7456 (2019). https://doi.org/10.1038/s41388-019-0963-7

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