3sl9 › Citations

An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid.

<div class='caption-title'>A plus–minus screen for compounds blocking ARD-HD2 binding.</div>
<div class='caption-title'>CA inhibits the BCL9-β-catenin interaction.</div>
<div class='caption-title'>R4 contains the molecular target of CA.</div>
de la Roche M, Rutherford TJ, Gupta D, Veprintsev DB, Saxty B, Freund SM, Bienz M
OpenAccess logo Nat Commun 3 680 (2012)
Cited: 80 times
EuropePMC logo PMID: 22353711

Abstract

Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin.

Reviews - 3sl9 mentioned but not cited (1)

  1. Emerging Direct Targeting β-Catenin Agents. Nalli M, Masci D, Urbani A, La Regina G, Silvestri R. Molecules 27 7735 (2022)

Articles - 3sl9 mentioned but not cited (12)

  1. An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid. de la Roche M, Rutherford TJ, Gupta D, Veprintsev DB, Saxty B, Freund SM, Bienz M. Nat Commun 3 680 (2012)
  2. Pharmacological inhibition of β-catenin/BCL9 interaction overcomes resistance to immune checkpoint blockades by modulating Treg cells. Feng M, Jin JQ, Xia L, Xiao T, Mei S, Wang X, Huang X, Chen J, Liu M, Chen C, Rafi S, Zhu AX, Feng YX, Zhu D. Sci Adv 5 eaau5240 (2019)
  3. Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors. Wisniewski JA, Yin J, Teuscher KB, Zhang M, Ji H. ACS Med Chem Lett 7 508-513 (2016)
  4. Gene expression and pathway analysis of CTNNB1 in cancer and stem cells. Tanabe S, Kawabata T, Aoyagi K, Yokozaki H, Sasaki H. World J Stem Cells 8 384-395 (2016)
  5. Identifying tandem Ankyrin repeats in protein structures. Chakrabarty B, Parekh N. BMC Bioinformatics 15 6599 (2014)
  6. A general-purpose Nanohybrid fabricated by Polymeric Au(I)-peptide precursor to wake the function of Peptide Therapeutics. Yan J, Ji F, Yan S, You W, Ma F, Li F, Huang Y, Liu W, He W. Theranostics 10 8513-8527 (2020)
  7. Antitumor Activity of Nitazoxanide against Colon Cancers: Molecular Docking and Experimental Studies Based on Wnt/β-Catenin Signaling Inhibition. Abd El-Fadeal NM, Nafie MS, K El-Kherbetawy M, El-Mistekawy A, Mohammad HMF, Elbahaie AM, Hashish AA, Alomar SY, Aloyouni SY, El-Dosoky M, Morsy KM, Zaitone SA. Int J Mol Sci 22 5213 (2021)
  8. Cytotoxic Evaluation, Molecular Docking, and 2D-QSAR Studies of Dihydropyrimidinone Derivatives as Potential Anticancer Agents. Altaf R, Nadeem H, Ilyas U, Iqbal J, Paracha RZ, Zafar H, Paiva-Santos AC, Sulaiman M, Raza F. J Oncol 2022 7715689 (2022)
  9. The Effect of Liposomal Diallyl Disulfide and Oxaliplatin on Proliferation of Colorectal Cancer Cells: In Vitro and In Silico Analysis. Alrumaihi F, Khan MA, Babiker AY, Alsaweed M, Azam F, Allemailem KS, Almatroudi AA, Ahamad SR, AlSuhaymi N, Alsugoor MH, Algefary AN, Khan A. Pharmaceutics 14 236 (2022)
  10. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer. Tanton H, Sewastianik T, Seo HS, Remillard D, Pierre RS, Bala P, Aitymbayev D, Dennis P, Adler K, Geffken E, Yeoh Z, Vangos N, Garbicz F, Scott D, Sethi N, Bradner J, Dhe-Paganon S, Carrasco RD. Sci Adv 8 eabm3108 (2022)
  11. Experimental and Theoretical Insights on Chemopreventive Effect of the Liposomal Thymoquinone Against Benzo[a]pyrene-Induced Lung Cancer in Swiss Albino Mice. Khan A, Alsahli MA, Aljasir MA, Maswadeh H, Mobark MA, Azam F, Allemailem KS, Alrumaihi F, Alhumaydhi FA, Almatroudi AA, AlSuhaymi N, Khan MA. J Inflamm Res 15 2263-2280 (2022)
  12. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)


Reviews citing this publication (31)

  1. Wnt signaling in stem and cancer stem cells. Holland JD, Klaus A, Garratt AN, Birchmeier W. Curr Opin Cell Biol 25 254-264 (2013)
  2. Wnt/β-catenin signalling in prostate cancer. Kypta RM, Waxman J. Nat Rev Urol 9 418-428 (2012)
  3. WNT Signaling in Cardiac and Vascular Disease. Foulquier S, Daskalopoulos EP, Lluri G, Hermans KCM, Deb A, Blankesteijn WM. Pharmacol Rev 70 68-141 (2018)
  4. Targeting the β-catenin nuclear transport pathway in cancer. Jamieson C, Sharma M, Henderson BR. Semin Cancer Biol 27 20-29 (2014)
  5. Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols. Moore J, Yousef M, Tsiani E. Nutrients 8 E731 (2016)
  6. Pharmacological modulation of beta-catenin and its applications in cancer therapy. Thakur R, Mishra DP. J Cell Mol Med 17 449-456 (2013)
  7. Wnt/β-catenin signaling in cancers and targeted therapies. Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Signal Transduct Target Ther 6 307 (2021)
  8. Modulating the wnt signaling pathway with small molecules. Tran FH, Zheng JJ. Protein Sci 26 650-661 (2017)
  9. Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia. Li BE, Ernst P. Exp Hematol 42 995-1012 (2014)
  10. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Zhao H, Ming T, Tang S, Ren S, Yang H, Liu M, Tao Q, Xu H. Mol Cancer 21 144 (2022)
  11. Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy. Lyou Y, Habowski AN, Chen GT, Waterman ML. Br J Pharmacol 174 4589-4599 (2017)
  12. The WNT/β-catenin dependent transcription: A tissue-specific business. Söderholm S, Cantù C. WIREs Mech Dis 13 e1511 (2021)
  13. Direct targeting of β-catenin in the Wnt signaling pathway: Current progress and perspectives. Wang Z, Li Z, Ji H. Med Res Rev 41 2109-2129 (2021)
  14. Multiple pro-apoptotic targets of abietane diterpenoids from Salvia species. Akaberi M, Mehri S, Iranshahi M. Fitoterapia 100 118-132 (2015)
  15. Wnt Drug Discovery: Weaving Through the Screens, Patents and Clinical Trials. Lu B, Green BA, Farr JM, Lopes FC, Van Raay TJ. Cancers (Basel) 8 E82 (2016)
  16. Protein-protein interaction modulator drug discovery: past efforts and future opportunities using a rich source of low- and high-throughput screening assays. Gul S, Hadian K. Expert Opin Drug Discov 9 1393-1404 (2014)
  17. E-Cadherin/β-Catenin Complex: A Target for Anticancer and Antimetastasis Plants/Plant-derived Compounds. Tafrihi M, Nakhaei Sistani R. Nutr Cancer 69 702-722 (2017)
  18. Crosstalk between microRNA30a/b/c/d/e-5p and the canonical Wnt pathway: implications for multiple myeloma therapy. Zhao JJ, Carrasco RD. Cancer Res 74 5351-5358 (2014)
  19. Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views. Kim MJ, Huang Y, Park JI. Cancers (Basel) 12 E3638 (2020)
  20. Discovery of chemical probes that suppress Wnt/β-catenin signaling through high-throughput screening. Yamaguchi K, Nagatoishi S, Tsumoto K, Furukawa Y. Cancer Sci 111 783-794 (2020)
  21. Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy. Li Z, Liu Y, Fang X, Shu Z. Int J Nanomedicine 16 1631-1661 (2021)
  22. Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer. Oliveira LFS, Predes D, Borges HL, Abreu JG. Cancers (Basel) 14 403 (2022)
  23. The structural biology of canonical Wnt signalling. Agostino M, Pohl SÖ. Biochem Soc Trans 48 1765-1780 (2020)
  24. Sporadic desmoid tumors in the pediatric population: A single center experience and review of the literature. Shkalim Zemer V, Toledano H, Kornreich L, Freud E, Atar E, Avigad S, Feinberg-Gorenshtein G, Fichman S, Issakov J, Dujovny T, Yaniv I, Ash S. J Pediatr Surg 52 1637-1641 (2017)
  25. Biophysical Survey of Small-Molecule β-Catenin Inhibitors: A Cautionary Tale. McCoy MA, Spicer D, Wells N, Hoogewijs K, Fiedler M, Baud MGJ. J Med Chem 65 7246-7261 (2022)
  26. Helical sulfono-γ-AApeptides with predictable functions in protein recognition. Sang P, Shi Y, Wei L, Cai J. RSC Chem Biol 3 805-814 (2022)
  27. β-catenin inhibitors in cancer therapeutics: intricacies and way forward. Dev A, Vachher M, Prasad CP. Bioengineered 14 2251696 (2023)
  28. A New Wave of Targeting 'Undruggable' Wnt Signaling for Cancer Therapy: Challenges and Opportunities. Park WJ, Kim MJ. Cells 12 1110 (2023)
  29. The Wnt-dependent and Wnt-independent functions of BCL9 in development, tumorigenesis, and immunity: Implications in therapeutic opportunities. Wu M, Dong H, Xu C, Sun M, Gao H, Bu F, Chen J. Genes Dis 11 701-710 (2024)
  30. Therapeutic vulnerabilities of cancer stem cells and effects of natural products. Reisenauer KN, Aroujo J, Tao Y, Ranganathan S, Romo D, Taube JH. Nat Prod Rep 40 1432-1456 (2023)
  31. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases. Talukdar PD, Chatterji U. Signal Transduct Target Ther 8 427 (2023)

Articles citing this publication (36)

  1. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, Xiang X, Deng ZB, Wang B, Zhang L, Roth M, Welti R, Mobley J, Jun Y, Miller D, Zhang HG. Mol Ther 21 1345-1357 (2013)
  2. Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Takada K, Zhu D, Bird GH, Sukhdeo K, Zhao JJ, Mani M, Lemieux M, Carrasco DE, Ryan J, Horst D, Fulciniti M, Munshi NC, Xu W, Kung AL, Shivdasani RA, Walensky LD, Carrasco DR. Sci Transl Med 4 148ra117 (2012)
  3. Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Tao W, Chu C, Zhou W, Huang Z, Zhai K, Fang X, Huang Q, Zhang A, Wang X, Yu X, Huang H, Wu Q, Sloan AE, Yu JS, Li X, Stark GR, Rich JN, Bao S. Nat Commun 11 3015 (2020)
  4. Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling. Hwang SY, Deng X, Byun S, Lee C, Lee SJ, Suh H, Zhang J, Kang Q, Zhang T, Westover KD, Mandinova A, Lee SW. Cell Rep 16 28-36 (2016)
  5. The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. Zhu D, Wang Z, Zhao JJ, Calimeri T, Meng J, Hideshima T, Fulciniti M, Kang Y, Ficarro SB, Tai YT, Hunter Z, McMilin D, Tong H, Mitsiades CS, Wu CJ, Treon SP, Dorfman DM, Pinkus G, Munshi NC, Tassone P, Marto JA, Anderson KC, Carrasco RD. Nat Med 21 572-580 (2015)
  6. LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors. de la Roche M, Ibrahim AE, Mieszczanek J, Bienz M. Cancer Res 74 1495-1505 (2014)
  7. Structural and thermodynamic characterization of cadherin·β-catenin·α-catenin complex formation. Pokutta S, Choi HJ, Ahlsen G, Hansen SD, Weis WI. J Biol Chem 289 13589-13601 (2014)
  8. Carnosic acid biosynthesis elucidated by a synthetic biology platform. Ignea C, Athanasakoglou A, Ioannou E, Georgantea P, Trikka FA, Loupassaki S, Roussis V, Makris AM, Kampranis SC. Proc Natl Acad Sci U S A 113 3681-3686 (2016)
  9. BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer. Moor AE, Anderle P, Cantù C, Rodriguez P, Wiedemann N, Baruthio F, Deka J, André S, Valenta T, Moor MB, Győrffy B, Barras D, Delorenzi M, Basler K, Aguet M. EBioMedicine 2 1932-1943 (2015)
  10. Constitutive scaffolding of multiple Wnt enhanceosome components by Legless/BCL9. van Tienen LM, Mieszczanek J, Fiedler M, Rutherford TJ, Bienz M. Elife 6 e20882 (2017)
  11. Inhibition of β-catenin/B cell lymphoma 9 protein-protein interaction using α-helix-mimicking sulfono-γ-AApeptide inhibitors. Sang P, Zhang M, Shi Y, Li C, Abdulkadir S, Li Q, Ji H, Cai J. Proc Natl Acad Sci U S A 116 10757-10762 (2019)
  12. Carnosic acid attenuates RANKL-induced oxidative stress and osteoclastogenesis via induction of Nrf2 and suppression of NF-κB and MAPK signalling. Thummuri D, Naidu VGM, Chaudhari P. J Mol Med (Berl) 95 1065-1076 (2017)
  13. Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger. Miller TC, Rutherford TJ, Birchall K, Chugh J, Fiedler M, Bienz M. ACS Chem Biol 9 2864-2874 (2014)
  14. Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development. Cantù C, Zimmerli D, Hausmann G, Valenta T, Moor A, Aguet M, Basler K. Genes Dev 28 1879-1884 (2014)
  15. Self-Assembly of Therapeutic Peptide into Stimuli-Responsive Clustered Nanohybrids for Cancer-Targeted Therapy. He W, Wang S, Yan J, Qu Y, Jin L, Sui F, Li Y, You W, Yang G, Yang Q, Ji M, Shao Y, Ma PX, Lu W, Hou P. Adv Funct Mater 29 1807736 (2019)
  16. JRK is a positive regulator of β-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer. Pangon L, Ng I, Giry-Laterriere M, Currey N, Morgan A, Benthani F, Tran PN, Al-Sohaily S, Segelov E, Parker BL, Cowley MJ, Wright DC, St Heaps L, Carey L, Rooman I, Kohonen-Corish MR. Oncogene 35 2834-2841 (2016)
  17. CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling. Chen J, Rajasekaran M, Xia H, Kong SN, Deivasigamani A, Sekar K, Gao H, Swa HL, Gunaratne J, Ooi LL, Xie T, Hong W, Hui KM. EMBO J 37 e99395 (2018)
  18. BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins. Jiang M, Kang Y, Sewastianik T, Wang J, Tanton H, Alder K, Dennis P, Xin Y, Wang Z, Liu R, Zhang M, Huang Y, Loda M, Srivastava A, Chen R, Liu M, Carrasco RD. Nat Commun 11 19 (2020)
  19. Functional inhibition of β-catenin-mediated Wnt signaling by intracellular VHH antibodies. Newnham LE, Wright MJ, Holdsworth G, Kostarelos K, Robinson MK, Rabbitts TH, Lawson AD. MAbs 7 180-191 (2015)
  20. Inhibiting β-Catenin by β-Carboline-Type MDM2 Inhibitor for Pancreatic Cancer Therapy. Qin JJ, Wang W, Li X, Deokar H, Buolamwini JK, Zhang R. Front Pharmacol 9 5 (2018)
  21. USP9X-mediated deubiquitination of B-cell CLL/lymphoma 9 potentiates Wnt signaling and promotes breast carcinogenesis. Shang Z, Zhao J, Zhang Q, Cao C, Tian S, Zhang K, Liu L, Shi L, Yu N, Yang S. J Biol Chem 294 9844-9857 (2019)
  22. Structure-Based Optimization of Small-Molecule Inhibitors for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction. Zhang M, Wang Z, Zhang Y, Guo W, Ji H. J Med Chem 61 2989-3007 (2018)
  23. Sulfono-γ-AApeptides as Helical Mimetics: Crystal Structures and Applications. Sang P, Shi Y, Huang B, Xue S, Odom T, Cai J. Acc Chem Res 53 2425-2442 (2020)
  24. Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models. Mieszczanek J, van Tienen LM, Ibrahim AEK, Winton DJ, Bienz M. Nat Commun 10 724 (2019)
  25. Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. Rodriguez-Blanco J, Pednekar L, Penas C, Li B, Martin V, Long J, Lee E, Weiss WA, Rodriguez C, Mehrdad N, Nguyen DM, Ayad NG, Rai P, Capobianco AJ, Robbins DJ. Oncogene 36 6306-6314 (2017)
  26. SOX7 Suppresses Wnt Signaling by Disrupting β-Catenin/BCL9 Interaction. Fan R, He H, Yao W, Zhu Y, Zhou X, Gui M, Lu J, Xi H, Deng Z, Fan M. DNA Cell Biol 37 126-132 (2018)
  27. Overexpression of Pygopus-2 is required for canonical Wnt activation in human lung cancer. Zhou SY, Xu ML, Wang SQ, Zhang F, Wang L, Wang HQ. Oncol Lett 7 233-238 (2014)
  28. Production of the forskolin precursor 11β-hydroxy-manoyl oxide in yeast using surrogate enzymatic activities. Ignea C, Ioannou E, Georgantea P, Trikka FA, Athanasakoglou A, Loupassaki S, Roussis V, Makris AM, Kampranis SC. Microb Cell Fact 15 46 (2016)
  29. BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression. Elsarraj HS, Hong Y, Limback D, Zhao R, Berger J, Bishop SC, Sabbagh A, Oppenheimer L, Harper HE, Tsimelzon A, Huang S, Hilsenbeck SG, Edwards DP, Fontes J, Fan F, Madan R, Fangman B, Ellis A, Tawfik O, Persons DL, Fields T, Godwin AK, Hagan CR, Swenson-Fields K, Coarfa C, Thompson J, Behbod F. NPJ Breast Cancer 6 12 (2020)
  30. Callicarpa longissima extract, carnosol-rich, potently inhibits melanogenesis in B16F10 melanoma cells. Yamahara M, Sugimura K, Kumagai A, Fuchino H, Kuroi A, Kagawa M, Itoh Y, Kawahara H, Nagaoka Y, Iida O, Kawahara N, Takemori H, Watanabe H. J Nat Med 70 28-35 (2016)
  31. Getting a Grip on the Undrugged: Targeting β-Catenin with Fragment-Based Methods. Kessler D, Mayer M, Zahn SK, Zeeb M, Wöhrle S, Bergner A, Bruchhaus J, Ciftci T, Dahmann G, Dettling M, Döbel S, Fuchs JE, Geist L, Hela W, Kofink C, Kousek R, Moser F, Puchner T, Rumpel K, Scharnweber M, Werni P, Wolkerstorfer B, Breitsprecher D, Baaske P, Pearson M, McConnell DB, Böttcher J. ChemMedChem 16 1420-1424 (2021)
  32. Testicular Caspase-3 and β-Catenin Regulators Predicted via Comparative Metabolomics and Docking Studies. Hifnawy MS, Aboseada MA, Hassan HM, AboulMagd AM, Tohamy AF, Abdel-Kawi SH, Rateb ME, El Naggar EMB, Liu M, Quinn RJ, Alhadrami HA, Abdelmohsen UR. Metabolites 10 E31 (2020)
  33. Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction. Wang Z, Zhang M, Quereda V, Frydman SM, Ming Q, Luca VC, Duckett DR, Ji H. J Med Chem 64 12109-12131 (2021)
  34. A de novo dual-targeting supramolecular self-assembly peptide against pulmonary metastasis of melanoma. Wang J, Zheng X, Fu X, Jiang A, Yao Y, He W. Theranostics 13 3844-3855 (2023)
  35. Modulating β-catenin/BCL9 interaction with cell-membrane-camouflaged carnosic acid to inhibit Wnt pathway and enhance tumor immune response. Gao R, Zheng X, Jiang A, He W, Liu T. Front Immunol 14 1274223 (2023)
  36. New ZW4864 Derivatives as Small-Molecule Inhibitors for the β-Catenin/BCL9 Protein-Protein Interaction. Wang Z, Zhang M, Thompson HM, Ji H. ACS Med Chem Lett 13 865-870 (2022)


Quick links