Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/β-catenin/CBP signaling pathway

Oncogene volume 38, pages 5516–5529 (2019)Cite this article

Subjects

Abstract

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/β-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/β-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of β-catenin. AKIP1 interacted with and sustained β-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of β-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of β-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/β-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/β-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.

    Article  Google Scholar 

  2. Marquardt JU, Thorgeirsson SS. SnapShot: hepatocellular carcinoma. Cancer Cell. 2014;25:550e551.

    Google Scholar 

  3. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

    Article  CAS  Google Scholar 

  4. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7.

    Article  Google Scholar 

  5. Sasaki Y, Yamada T, Tanaka H, Ohigashi H, Eguchi H, Yano M, et al. Risk of recurrence in a long-term follow-up after surgery in 417 patients with hepatitis B- or hepatitis C-related hepatocellular carcinoma. Ann Surg. 2006;244:771–80.

    Article  Google Scholar 

  6. Valenta T, Hausmann G, Basler K. The many faces and functions of beta-catenin. EMBO J. 2012;31:2714–36.

    Article  CAS  Google Scholar 

  7. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–80.

    Article  CAS  Google Scholar 

  8. Nguyen DX, Chiang AC, Zhang XH, Kim JY, Kris MG, Ladanyi M, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138:51–62.

    Article  CAS  Google Scholar 

  9. Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet. 2004;5:691–701.

    Article  CAS  Google Scholar 

  10. Arce L, Yokoyama NN, Waterman ML. Diversity of LEF/TCF action in development and disease. Oncogene. 2006;25:7492–504.

    Article  CAS  Google Scholar 

  11. Takemaru KI, Moon RT. The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol. 2000;149:249–54.

    Article  CAS  Google Scholar 

  12. Hecht A, Vleminckx K, Stemmler MP, van Roy F, Kemler R. The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000;19:1839–50.

    Article  CAS  Google Scholar 

  13. Anson M, Crain-Denoyelle AM, Baud V, Chereau F, Gougelet A, Terris B, et al. Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest. 2012;122:586–99.

    Article  CAS  Google Scholar 

  14. Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59:1107–17.

    Article  CAS  Google Scholar 

  15. Chen J, Rajasekaran M, Xia H, Zhang X, Kong SN, Sekar K, et al. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/beta-catenin signalling pathway. Gut. 2016;65:1522–34.

    Article  CAS  Google Scholar 

  16. Kitching R, Li H, Wong MJ, Kanaganayakam S, Kahn H, Seth A. Characterization of a novel human breast cancer associated gene (BCA3) encoding an alternatively spliced proline-rich protein. Biochim Biophysica Acta. 2003;1625:116–21.

    Article  CAS  Google Scholar 

  17. Lin C, Song L, Liu A, Gong H, Lin X, Wu J, et al. Overexpression of AKIP1 promotes angiogenesis and lymphangiogenesis in human esophageal squamous cell carcinoma. Oncogene. 2015;34:384–93.

    Article  CAS  Google Scholar 

  18. Tian J, Tang ZY, Ye SL, Liu YK, Lin ZY, Chen J, et al. New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer. 1999;81:814–21.

    Article  CAS  Google Scholar 

  19. Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, et al. Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 2001;7:630–6.

    Article  CAS  Google Scholar 

  20. Sastri M, Barraclough DM, Carmichael PT, Taylor SS. A-kinase-interacting protein localizes protein kinase A in the nucleus. Proc Natl Acad Sci USA. 2005;102:349–54.

    Article  CAS  Google Scholar 

  21. Wang W, Xu L, Liu P, Jairam K, Yin Y, Chen K, et al. Blocking Wnt secretion reduces growth of hepatocellular carcinoma cell lines mostly independent of beta-catenin signaling. Neoplasia. 2016;18:711–23.

    Article  CAS  Google Scholar 

  22. Henderson BR. Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover. Nat Cell Biol. 2000;2:653–60.

    Article  CAS  Google Scholar 

  23. Xing Y, Clements WK, Le Trong I, Hinds TR, Stenkamp R, Kimelman D, et al. Crystal structure of a beta-catenin/APC complex reveals a critical role for APC phosphorylation in APC function. Mol Cell. 2004;15:523–33.

    Article  CAS  Google Scholar 

  24. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem. 2006;281:9971–6.

    Article  CAS  Google Scholar 

  25. Dema A, Schroter MF, Perets E, Skroblin P, Moutty MC, Deak VA, et al. The A-kinase anchoring protein (AKAP) glycogen synthase kinase 3beta interaction protein (GSKIP) regulates beta-catenin through its interactions with both protein kinase A (PKA) and GSK3beta. J Biol Chem. 2016;291:19618–30.

    Article  CAS  Google Scholar 

  26. Li CC, Le K, Kato J, Moss J, Vaughan M. Enhancement of beta-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals. Proc Natl Acad Sci USA. 2016;113:5946–51.

    Article  CAS  Google Scholar 

  27. Gao N, Asamitsu K, Hibi Y, Ueno T, Okamoto T. AKIP1 enhances NF-kappaB-dependent gene expression by promoting the nuclear retention and phosphorylation of p65. J Biol Chem. 2008;283:7834–43.

    Article  CAS  Google Scholar 

  28. Ma D, Li M, Su J, Zhang S. BCA3 contributes to the malignant progression of hepatocellular carcinoma through AKT activation and NF-kappaB translocation. Exp Cell Res. 2018;362:142–51.

    Article  CAS  Google Scholar 

  29. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6:674–87.

    Article  CAS  Google Scholar 

  30. Huang H, Fujii H, Sankila A, Mahler-Araujo BM, Matsuda M, Cathomas G, et al. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol. 1999;155:1795–801.

    Article  CAS  Google Scholar 

  31. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–92.

    Article  CAS  Google Scholar 

  32. Rosin-Arbesfeld R, Townsley F, Bienz M. The APC tumour suppressor has a nuclear export function. Nature. 2000;406:1009–12.

    Article  CAS  Google Scholar 

  33. Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science. 1993;262:1734–7.

    Article  CAS  Google Scholar 

  34. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.

    Article  CAS  Google Scholar 

  35. Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120:1763–73.

    Article  CAS  Google Scholar 

  36. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.

    Article  CAS  Google Scholar 

  37. Anastas JN, Moon RT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2013;13:11–26.

    Article  CAS  Google Scholar 

  38. Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA. 2004;101:12682–7.

    Article  CAS  Google Scholar 

  39. Nagaraj AB, Joseph P, Kovalenko O, Singh S, Armstrong A, Redline R, et al. Critical role of Wnt/beta-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget. 2015;6:23720–34.

    Article  Google Scholar 

  40. Gang EJ, Hsieh YT, Pham J, Zhao Y, Nguyen C, Huantes S, et al. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene. 2014;33:2169–78.

    Article  CAS  Google Scholar 

  41. Wend P, Fang L, Zhu Q, Schipper JH, Loddenkemper C, Kosel F, et al. Wnt/beta-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. EMBO J. 2013;32:1977–89.

    Article  CAS  Google Scholar 

  42. Cui YM, Jiao HL, Ye YP, Chen CM, Wang JX, Tang N, et al. FOXC2 promotes colorectal cancer metastasis by directly targeting MET. Oncogene. 2015;34:4379–90.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by The Natural Science Foundation of China (Nos. 81572688, 81872386, 81530082, 81773106, 91740118, 81830082, 91740119, 91529301, 81621004, 81472546); The Natural Science Foundation of Guangdong Province (Nos. 2016A030308002, 2018B030311060, 2018B030311009); The Science and Technology Program of Guangzhou (201504010015); Guangzhou Science and Technology Plan Projects (201803010098); and The Fundamental Research Funds for the Central Universities [No. 17ykjc02].

Author information

Authors and Affiliations

  1. Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, Guangdong, China

    Yanmei Cui, Xianqiu Wu, Chuyong Lin, Xin Zhang, Liping Ye, Liangliang Ren, Yue Li & Libing Song

  2. Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, China

    Yanmei Cui

  3. Department of Radiation Oncology, Nanfang Hospital of Sourthern Medical University, 510515, Guangzhou, Guangdong, China

    Min Chen & Jian Guan

  4. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China

    Meisongzhu Yang & Jun Li

  5. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, Guangdong, China

    Mengfeng Li

Authors
  1. Yanmei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xianqiu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuyong Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Liping Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liangliang Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Min Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Meisongzhu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mengfeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jian Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Libing Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jun Li, Jian Guan or Libing Song.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, Y., Wu, X., Lin, C. et al. AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/β-catenin/CBP signaling pathway. Oncogene 38, 5516–5529 (2019). https://doi.org/10.1038/s41388-019-0807-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0807-5

This article is cited by

Search

Advanced search

Quick links