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Global analysis of RNA-binding proteins identifies a positive feedback loop between LARP1 and MYC that promotes tumorigenesis

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Abstract

In addition to genomic alterations, aberrant changes in post-transcriptional regulation can modify gene function and drive cancer development. RNA-binding proteins (RBPs) are a large class of post-transcriptional regulators that have been increasingly implicated in carcinogenesis. By integrating multi-omics data, we identify LARP1 as one of the most upregulated RBPs in colorectal cancer (CRC) and demonstrate its oncogenic properties. We perform LARP1:RNA interactome profiling and unveil a previously unexplored role for LARP1 in targeting the 3′UTR of oncogenes in CRC. Notably, we identify the proto-oncogenic transcription factor MYC as a key LARP1-regulated target. Our data show that LARP1 positively modulates MYC expression by associating with its 3′UTR. In addition, antisense oligonucleotide-mediated blocking of the interaction between LARP1 and the MYC 3′UTR reduces MYC expression and in vitro CRC growth. Furthermore, a systematic analysis of LARP1:protein interactions reveals IGF2BP3 and YBX1 as LARP1-interacting proteins that also regulate MYC expression and CRC development. Finally, we demonstrate that MYC reciprocally modulates LARP1 expression by targeting its enhancer. In summary, our data reveal a critical, previously uncharacterized role of LARP1 in promoting CRC tumorigenesis, validate its direct regulation of the proto-oncogene MYC and delineate a model of the positive feedback loop between MYC and LARP1 that promotes CRC growth and development.

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References

  1. Wurth L (2012) Versatility of RNA-binding proteins in cancer. Comp Funct Genomics 2012:178525

    PubMed  PubMed Central  Google Scholar 

  2. Hentze MW et al (2018) A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol 19(5):327–341

    CAS  PubMed  Google Scholar 

  3. Audic Y, Hartley RS (2004) Post-transcriptional regulation in cancer. Biol Cell 96(7):479–498

    CAS  PubMed  Google Scholar 

  4. Arnold M et al (2017) Global patterns and trends in colorectal cancer incidence and mortality. Gut 66(4):683–691

    Article  PubMed  Google Scholar 

  5. Kuipers EJ et al (2015) Colorectal cancer. Nat Rev Dis Primers 1:15065

    PubMed  PubMed Central  Google Scholar 

  6. Xie C et al (2013) LARP1 predict the prognosis for early-stage and AFP-normal hepatocellular carcinoma. J Transl Med 11:272

    PubMed  PubMed Central  Google Scholar 

  7. Bousquet-Antonelli C, Deragon JM (2009) A comprehensive analysis of the La-motif protein superfamily. RNA 15(5):750–764

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hopkins TG et al (2016) The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer. Nucleic Acids Res 44(3):1227–1246

    CAS  PubMed  Google Scholar 

  9. Mura M et al (2015) LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression. Oncogene 34(39):5025–5036

    CAS  PubMed  Google Scholar 

  10. Ye L et al (2016) Overexpression of LARP1 predicts poor prognosis of colorectal cancer and is expected to be a potential therapeutic target. Tumour Biol 37(11):14585–14594

    CAS  PubMed  Google Scholar 

  11. Fonseca BD et al (2015) La-related Protein 1 (LARP1) represses terminal Oligopyrimidine (TOP) mRNA translation downstream of mTOR Complex 1 (mTORC1). J Biol Chem 290(26):15996–16020

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Tcherkezian J et al (2014) Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5’TOP mRNA translation. Genes Dev 28(4):357–371

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Butter F et al (2009) Unbiased RNA–protein interaction screen by quantitative proteomics. Proc Natl Acad Sci USA 106(26):10626–10631

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoon JH, Srikantan S, Gorospe M (2012) MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. Methods 58(2):81–87

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Meisenheimer KM, Koch TH (1997) Photocross-linking of nucleic acids to associated proteins. Crit Rev Biochem Mol Biol 32(2):101–140

    CAS  PubMed  Google Scholar 

  16. Van Nostrand EL et al (2016) Robust transcriptome-wide discovery of RNA-binding protein binding sites with enhanced CLIP (eCLIP). Nat Methods 13(6):508–514

    PubMed  PubMed Central  Google Scholar 

  17. Lovci MT et al (2013) Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges. Nat Struct Mol Biol 20(12):1434–1442

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26(6):841–842

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Li Q, Brown JB, Huang H, Bickel PJ (2011) Measuring reproducibility of high throughput experiments. Ann Appl Stat 5:1752–1779

    Google Scholar 

  20. Liao Y et al (2019) WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res 47(W1):W199–W205

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cox J, Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26(12):1367–1372

    CAS  PubMed  Google Scholar 

  22. Lee TI et al (2006) Chromatin immunoprecipitation and microarray-based analysis of protein location. Nat Protocol 1(2):729–748

    CAS  Google Scholar 

  23. Zhang B et al (2020) A comprehensive expression landscape of RNA-binding proteins (RBPs) across 16 human cancer types. RNA Biol 17(2):211–226

    CAS  PubMed  Google Scholar 

  24. Lahr RM et al (2015) The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5’TOP sequence. Nucleic Acids Res 43(16):8077–8088

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lahr RM et al (2017) La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs. Elife. https://doi.org/10.7554/eLife.24146

    Article  PubMed  PubMed Central  Google Scholar 

  26. Roy HK et al (2002) AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23(1):201–205

    CAS  PubMed  Google Scholar 

  27. Rochlitz CF, Herrmann R, de Kant E (1996) Overexpression and amplification of c-myc during progression of human colorectal cancer. Oncology 53(6):448–454

    CAS  PubMed  Google Scholar 

  28. Erisman MD et al (1985) Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol 5(8):1969–1976

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang H, Birkenbach M, Hart J (2000) Expression of Jun family members in human colorectal adenocarcinoma. Carcinogenesis 21(7):1313–1317

    CAS  PubMed  Google Scholar 

  30. Arber N et al (1996) Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis. Gastroenterology 110(3):669–674

    CAS  PubMed  Google Scholar 

  31. Sebolt-Leopold JS et al (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 5(7):810–816

    CAS  PubMed  Google Scholar 

  32. Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337

    Google Scholar 

  33. Coller HA et al (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proc Natl Acad Sci USA 97(7):3260–3265

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Smith DR, Myint T, Goh HS (1993) Over-expression of the c-myc proto-oncogene in colorectal carcinoma. Br J Cancer 68(2):407–413

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mayr C, Bartel DP (2009) Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138(4):673–684

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Andres SF et al (2019) IMP1 3’ UTR shortening enhances metastatic burden in colorectal cancer. Carcinogenesis 40(4):569–579

    CAS  PubMed  Google Scholar 

  37. Li Z et al (2012) An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. Dev Cell 23(6):1176–1188

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Stavraka C, Blagden S (2015) The la-related proteins, a family with connections to cancer. Biomolecules 5(4):2701–2722

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kim A et al (2020) Inhibition of Y box binding protein 1 suppresses cell growth and motility in colorectal cancer. Mol Cancer Ther 19(2):479–489

    CAS  PubMed  Google Scholar 

  40. Xu W et al (2019) Increased IGF2BP3 expression promotes the aggressive phenotypes of colorectal cancer cells in vitro and vivo. J Cell Physiol 234(10):18466–18479

    CAS  PubMed  Google Scholar 

  41. Bommert KS et al (2013) The feed-forward loop between YB-1 and MYC is essential for multiple myeloma cell survival. Leukemia 27(2):441–450

    CAS  PubMed  Google Scholar 

  42. Palanichamy JK et al (2016) RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. J Clin Invest 126(4):1495–1511

    PubMed  PubMed Central  Google Scholar 

  43. Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Berman AJ et al (2021) Controversies around the function of LARP1. RNA Biol 18(2):207–217

    CAS  PubMed  Google Scholar 

  45. Chatel-Chaix L et al (2013) A host YB-1 ribonucleoprotein complex is hijacked by hepatitis C virus for the control of NS3-dependent particle production. J Virol 87(21):11704–11720

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang Y et al (2015) C1QBP negatively regulates the activation of oncoprotein YBX1 in the renal cell carcinoma as revealed by interactomics analysis. J Proteome Res 14(2):804–813

    CAS  PubMed  Google Scholar 

  47. Dejure FR et al (2017) The MYC mRNA 3’-UTR couples RNA polymerase II function to glutamine and ribonucleotide levels. EMBO J 36(13):1854–1868

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all past and present YT lab members for their constructive feedback on this project. We also thank Teck Kwang Lim from Protein and Proteomics Centre at the Department of Biological Sciences (DBS), NUS, and Charlene Chan from Cancer Science Institute of Singapore, for their assistance in performing the mass spectrometry analyses. In addition, we thank Avencia Sanchez-Mejias and Xiao Hong Chew for their technical assistance. Furthermore, we thank Shi Hao Tan from Cancer Science Institute of Singapore for his assistance in the design of the ChIP-qPCR experiments.

Funding

Y.T. is funded by a Singapore National Research Foundation Fellowship, a National Medical Research Council Open Fund—Individual Research Grant and a National University of Singapore President’s Assistant Professorship. Y.T., K.K. and D.K. are supported by the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s AcRF Tier 3 Grant (MOE2014-T3-1-006). G.W.Y. is funded by the National University of Singapore and National Research Foundation of Singapore. N.D. is supported by the NUS Research Scholarship. QYT is supported by a Cancer Science Institute of Singapore Research Scholarship. This research is supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, as well as the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s AcRF Tier 3 Grants, Grant number MOE2014-T3-1-006.

Author information

Author notes

  1. Zhi Hao Kwok

    Present address: Division of Pulmonary and Critical Care, Boston University, Boston, MA, 02118, USA

  2. Ng Desi and Qing Yun Tong contributed equally to this work.

  3. Velda Teh, Jia Jia Chan and Bin Zhang contributed equally to this work.

Authors and Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore

    Ng Desi, Qing Yun Tong, Velda Teh, Jia Jia Chan, Bin Zhang, Hossein Tabatabaeian, Chun You Lim, Zhi Hao Kwok, Henry Yang, Dennis Kappei & Yvonne Tay

  2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore

    Ng Desi, Hwee Tong Tan, Henry Yang, Dennis Kappei, Maxey Ching Ming Chung & Yvonne Tay

  3. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Hui Qing Tan, Katannya Kapeli, Wenhao Jin & Gene W. Yeo

  4. Department of Pathology, National University Health System, Singapore, Singapore

    Shi Wang

  5. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Bei-En Siew, Choon-Seng Chong & Ker-Kan Tan

  6. Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore

    Kuok-Chung Lee, Choon-Seng Chong & Ker-Kan Tan

  7. Department of Cellular and Molecular Medicine, Stem Cell Program and Institute for Genomic Medicine, University of California, La Jolla, San Diego, USA

    Gene W. Yeo

Authors
  1. Ng Desi
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Contributions

YT, ND, and JJC conceptualized and designed the project. ND and QYT designed and performed experiments, analyzed and interpreted data and generated figures. VT, JJC, BZ, HT, ZHK, and CYL designed and performed experiments and analyzed data. HQT, KK, WJ, and GWY performed, analyzed and interpreted the eCLIP experiments. BZ and HY performed bioinformatics analysis and interpretation. CYL, SW, PCLL, BES, KCL, CSC, and KKT obtained and processed the patient samples. HTT, MCMC and DK performed mass spectrometry experiments and analysis. ND, QYT, JJC, YT, KK, BZ, HTT, and DK wrote and edited the manuscript.

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Correspondence to Yvonne Tay.

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Desi, N., Tong, Q.Y., Teh, V. et al. Global analysis of RNA-binding proteins identifies a positive feedback loop between LARP1 and MYC that promotes tumorigenesis. Cell. Mol. Life Sci. 79, 147 (2022). https://doi.org/10.1007/s00018-021-04093-1

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