본문 바로가기
KERD
논문KCI 등재

YAP promotes global mRNA translation to fuel oncogenic growth despite starvation

노태영|Cho Suhyeon|Kim Yoon Ki|Lee Hyeonji|Hwang Daehee|Baek Seonguk|Chang Jeeyoon|Seol Taejun|Ku Bomin|Ha Hongseok|Lim Dae-Sik
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 2202-2215|DOI 10.1038/s12276-024-01316-w

0

조회

0

다운로드

0

인용

0

참고문헌

주제분류생화학

초록

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.

Abstract

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play fundamental roles in stem/progenitor cell expansion during homeostasis, and their dysregulation often leads to tissue overgrowth. Here, we show that YAP activation is sufficient to overcome the restriction of global protein synthesis induced by serum starvation, enabling cells to sustain proliferation and survival despite an unfavorable environment. Mechanistically, YAP/TAZ selectively promoted the mTORC1-dependent translation of mRNAs containing 5′ terminal oligopyrimidine (5′TOP) motifs, ultimately increasing the cellular polysome content. Interestingly, DNA damage-inducible transcript 4 (DDIT4), a negative regulator of mTORC1, was upregulated by serum starvation but repressed by YAP/TAZ. DDIT4 was sufficient to suppress the translation and transformative potential of uveal melanoma cells, which are often serum unresponsive due to G protein mutations. Our findings reveal a vital role for protein synthesis as a key modality of YAP/TAZ-induced oncogenic transformation and indicate the potential for targeting mTORC1 or translation to treat YAP/TAZ-driven malignancies.

참고문헌 (62)

  1. Dong, J., "Elucidation of a universal size-control mechanism in drosophila and mammals", Cell, 130, pp.1120~1133 (2007)
  2. Ni, L., "Structural basis for Mob1-dependent activation of the core Mst–Lats kinase cascade in Hippo signaling", Genes Dev, 29, pp.1416~1431 (2015)
  3. Zhao, B., "A coordinated phos phorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP)", Genes Dev, 24, pp.72~85 (2010)
  4. Yu, F. -X., "Hippo pathway in organ size control, tissue homeostasis, and cancer", Cell, 163, pp.811~828 (2015)
  5. Kim, T., "A basal-like breast cancer-specific role for SRF–IL6 in YAP-induced cancer stemness", Nat. Commun, 6, pp.10186~ (2015)
  6. Kim, M., "Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ", Cell Rep, 11, pp.270~282 (2015)
  7. Nolo, R., "The bantam microRNA is a target of the hippo tumor-suppressor pathway", Curr. Biol, 16, pp.1895~1904 (2006)
  8. Jang, W., "Mechanical cue‐induced YAP instructs Skp2‐dependent cell cycle exit and oncogenic signaling", EMBO J, 36, pp.2510~2528 (2017)
  9. Benham-Pyle, B. W., "Mechanical strain induces E-cadherin-dependent Yap1 and á-catenin activation to drive cell cycle entry", Science, 348, pp.1024~1027 (2015)
  10. Rosenbluh, J., "β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis", Cell, 151, pp.1457~1473 (2012)
  11. Kim, J., "YAP", TAZ regulates sprouting angiogenesis and vascular barrier maturation, 2017, pp.127, 3441~3461
  12. Ong, Y. T., "A YAP", TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth, 2022, ~
  13. Lamar, J. M., "The Hippo pathway target, YAP, promotes metastasis through its TEAD-interaction domain", Proc. Natl Acad. Sci. USA, 109 (2012)[DOI]
  14. Kim, M. H., "Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP", TAZ activation, 2015, pp.35, 462~478
  15. Mo, J. S., "Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway", Nat. Cell Biol, 17, pp.500~510 (2015)
  16. Zanconato, F., "Genome-wide association between YAP", TAZ, Nat. Cell Biol, pp.2015, 17[DOI]
  17. Palazzo, A. F., "Non-coding RNA: what is functional and what is junk?", Front. Genet, 5 (2015)[DOI]
  18. Levy, S., "Oligopyrimidine tract at the 5’ end of mammalian ribosomal protein mRNAs is required for their translational control", Proc. Natl Acad. Sci. USA, 88, pp.3319~3323 (1991)
  19. Liu, G. Y., "mTOR at the nexus of nutrition, growth, ageing and disease", Nat. Rev. Mol. Cell Biol, 21, pp.183~203 (2020)
  20. Sengupta, S., "Regulation of the mTOR complex 1pathway by nutrients, growth factors, and stress", Mol. Cell, 40, pp.310~322 (2010)
  21. Holz, M. K., "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events", Cell, 123, pp.569~580 (2005)
  22. Yanagiya, A., "Translational homeostasis via the mRNA cap-binding protein, eIF4E", Mol. Cell, 46, pp.847~858 (2012)
  23. Tumaneng, K., "YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29", Nat. Cell Biol, 14, pp.1322~1329 (2012)
  24. Gan, W., "LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control", Nat. Cell Biol, 22, pp.246~256 (2020)
  25. Hansen, C. G., "The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1", Cell Res, 25, pp.1299~1313 (2015)
  26. Jeon, H. Y., "Airway secretory cell fate conversion via YAP‐mTORC1‐depen dent essential amino acid metabolism", EMBO J, 41 (2022)[DOI]
  27. Inoki, K., "Rheb GTpase is a direct target of TSC2 GAP activity and regulates mTOR signaling", Genes Dev, 17, pp.1829~1834 (2003)
  28. Dennis, M. D., "Regulated in DNA damage and development 1(REDD1)promotes cell survival during serum deprivation by sustaining repression of signaling through the mechanistic target of rapamycin in complex 1(mTORC1)", Cell Signal, 25, pp.2709~2716 (2013)
  29. Brugarolas, J., "Regulation of mTOR function in response to hypoxia by REDD1and the TSC1", TSC2 tumor suppressor complex, 2004, pp.18, 2893~2904
  30. Wang, Z., "Dexamethasone-induced gene 2(dig2)is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals", J. Biol. Chem, 278, pp.27053~27058 (2003)
  31. Buttgereit, F., "A hierarchy of ATP-consuming processes in mam malian cells", Biochem. J, 312, pp.163~ (1995)
  32. Holcik, M., "Translational control in stress and apoptosis", Nat. Rev. Mol. Cell Biol, 6, pp.318~327 (2005)
  33. van Raamsdonk, C. D., "Mutations in GNA11 in uveal melanoma", N. Engl. J. Med, 363, pp.2191~2199 (2010)
  34. van Raamsdonk, C. D., "Frequent somatic mutations of GNAQ in uveal mel anoma and blue naevi", Nature, 457, pp.599~602 (2009)
  35. Csibi, A., "Hippo-YAP and mTOR pathways collaborate to regulate organ size", Nat. Cell Biol, 14, pp.1244~1245 (2012)
  36. Schmidt, E. K., "SUnSET, a nonradioactive method to monitor protein synthesis", Nat. Methods, 6, pp.275~277 (2009)
  37. Parrott, L. A., "Osmotic stress inhibits p70", 85 S6 kinase through activation of a protein phosphatase, 1999, pp.274, 24731~24736
  38. Lin, K. C., "Regulation of Hippo pathway transcription factor TEAD by p38MAPK-induced cytoplasmic translocation", Nat. Cell Biol, 19, pp.996~1002 (2017)
  39. Sengupta, S., "MTORC1 con trols fasting-induced ketogenesis and its modulation by ageing", Nature, 468, pp.1100~1106 (2010)
  40. Philippe, L., "Global analysis of LARP1 translation targets reveals tunable and dynamic features of 5′ TOP motifs", Proc. Natl Acad. Sci. USA, 117, pp.5319~5328 (2020)
  41. Wells, S., "Circularization of mRNA by eukaryotic translation initiation factors", Mol. Cell, 2, pp.135~140 (1998)
  42. Vega-Rubin-de-Celis, S., "Structural analysis and functional implications of the negative mTORC1 regulator REDD1", Biochemistry, 49, pp.2491~2501 (2010)
  43. Yu, F. X., "Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling", Cell, 150, pp.780~791 (2012)
  44. Yu, F. X., "Mutant Gq", 11 promote uveal melanoma tumorigenesis by acti vating YAP, 2014, pp.25, 822~830
  45. Vaidyanathan, S., "YAP regulates an SGK1", mTORC1, Dev. Cell, pp.2022, 57[DOI]
  46. Choi, W., "YAP", TAZ initiates gastric tumorigenesis via upregulation of MYC, 2018, pp.78, 3306~3320
  47. Croci, O., "Transcriptional integration of mitogenic and mechanical signals by Myc and YAP", Genes Dev, 31, pp.2017~2022 (2017)
  48. Mori, M., "Hippo signaling regulates microprocessor and links cell-density dependent mirna biogenesis to cancer", Cell, 156, pp.893~906 (2014)
  49. van Riggelen, J., "MYC as a regulator of ribosome bio genesis and protein synthesis", Nat. Rev. Cancer, 10, pp.301~309 (2010)
  50. Arabi, A., "c-Myc associates with ribosomal DNA and activates RNA poly merase I transcription", Nat. Cell Biol, 7, pp.303~310 (2005)
  51. Schaub, F. X., "Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas", Cell Syst, 6, pp.282~300 (2018)
  52. Murakami, H., "LATS2 is a tumor suppressor gene of malignant mesothe lioma", Cancer Res, 71, pp.873~883 (2011)
  53. Kapoor, A., "Yap1 activation enables bypass of oncogenic KRAS addiction in pancreatic cancer", Cell, 158, pp.185~197 (2014)
  54. Shao, D. D., "KRAS and YAP1 converge to regulate EMT and tumor survival", Cell, 158, pp.171~184 (2014)
  55. Cai, E. Y., "Selective translation of cell fate regulators mediates tolerance to broad oncogenic stress", Cell Stem Cell, 27, pp.270~283 (2020)
  56. Sekido, Y., "Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation", Pathol. Int, 61, pp.331~344 (2011)
  57. Mehra, R., "Biallelic alteration and dysregulation of the hippo pathway in mucinous tubular and spindle cell carcinoma of the kidney", Cancer Discov, 6, pp.1258~1266 (2016)
  58. Zhang, N., "The Merlin", NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals, 2010, pp.19, 27~38
  59. Plouffe, S. W., "Characterization of hippo pathway components by gene inactivation", Mol. Cell, 64, pp.993~1008 (2016)
  60. Ma, L., "Phosphor ylation and functional inactivation of TSC2 by Erk : implications for tuberous sclerosis and cancer pathogenesis", Cell, 121, pp.179~193 (2005)
  61. Petrova, V., "The hypoxic tumour microenvironment", Oncogenesis. Oncogenesis, 7 (2018)[DOI]
  62. Karsch-Bluman, A., "Tissue necrosis and its role in cancer progression", Oncogene, 38, pp.1920~1935 (2019)

관련 논문AI추천

Clinical implications of the Hippo-YAP pathway in multiple cancer contexts김한별, 명승재생화학분자생물학회 · BMB Reports2018 · 제51권 제3호The multifaceted role of YAP in the tumor microenvironment and its therapeutic implications in cancerKim Hyung-Sik, Nam Jeong-Seok생화학분자생물학회 · Experimental and Molecular Medicine2025 · 제57권 DNA binding partners of YAP/TAZ김민규, 배석철, 장주원생화학분자생물학회 · BMB Reports2018 · 제51권 제3호Hepatic Hippo signaling inhibits development of hepatocellular carcinomaXiaohui Wang, Yingzi Yang, Yuchen Liu대한간학회 · Clinical and Molecular Hepatology2020 · 제26권 제4호The role of extracellular biophysical cues in modulating the Hippo-YAP pathway모정순생화학분자생물학회 · BMB Reports2017 · 제50권 제2호Regulation of Hippo signaling by actin remodeling김준, 서지명생화학분자생물학회 · BMB Reports2018 · 제51권 제3호

이 간행물의 다른 논문 (218건)

Big data and deep learning for RNA biologyJeon Hyeonseong, Baek Daehyun, Hwang Hyeonseo, Yeo Nagyeongpp. 1-29RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinomaXu Yanan, Ke Shanjia, Lu Shounan, Bai Miaoyu, Yu Hongjun, Yin Bing, Wang Chaoqun, Feng Zhigang, Li Zihao, Huang Jingjing, Li Xinglong, Qian Baolin, Hua Yongliang, Fu Yao, Sun Bei, Wu Yaohua, Ma Yongpp. 1-14Molecular mechanisms of circular RNA translationKim Yoon Ki, Hwang Hyun Jungpp. 1-9The m6A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolismKim Ho, Yun Hye Jin, 이종호, Lee Su Bin, Kim Seok-Ho, Park Yun-Yong, Park Su Hwan, Ju Jin-Sung, Woo Hyunmin, Győrffy Balázs, Kim Eun-jeong, Han Hee Dong, Eyun Seong-ilpp. 1-15Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarctKim Ra Gyung, Cho Jongwook, Park Ji-Young, Kim Young Ro, Lee Min-Cheol, Kim Hyoung-Ihlpp. 1-11
원문 보기