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Disrupting CCDC137-mediated LZTS2 and β-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via β-catenin and AKT

Cell Death & Differentiation volume 32, pages 134–148 (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a highly heterogeneous solid tumor, with its biological characteristics intricately linked to the activation of oncogenes. This research specifically explored CCDC137, a molecule within the CCDC family exhibiting the closest association with HCC. Our investigation aimed to unravel the role, underlying mechanisms, and potential therapeutic implications of CCDC137 in the context of HCC. We observed a close correlation between elevated CCDC137 expression and poor prognosis in HCC patients, along with a promotive effect on HCC progression in vitro and in vivo. Mechanistically, we identified LZTS2, a negative regulator of β-catenin, as the binding protein of CCDC137. CCDC137 facilitated K48-linked poly-ubiquitination of LZTS2 at lysine 467 via recruiting E3 ubiquitin ligase β-TrCP in the nucleus, triggering AKT phosphorylation and activation of β-catenin pathway. Moreover, the 1-75 ___domain of CCDC137 was responsible for the formation of the CCDC137-LZTS2-β-TrCP complex. Subsequently, designed peptides targeting the 1-75 ___domain of CCDC137 to disrupt CCDC137-LZTS2 interaction demonstrated efficacy in inhibiting HCC progression. This promising outcome was further supported by HCC organoids and patient-derived xenograft (PDX) models, underscoring the potential clinical utility of the peptides. This study elucidated the mechanism of the CCDC137-LZTS2-β-TrCP protein complex in HCC and offered clinically significant therapeutic strategies targeting this complex.

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Fig. 1: Identification and characterization of CCDC137 in HCC.
Fig. 2: Knockdown of CCDC137 inhibits HCC progression in vitro and in vivo.
Fig. 3: CCDC137 enhances LZTS2 degradation to activate β-catenin and AKT pathways.
Fig. 4: CCDC137 recruits β-TrCP to bind with LZTS2, facilitating K48-linked poly-ubiquitination of LZTS2 in the nucleus.
Fig. 5: The 1–75 ___domain of CCDC137 is responsible for the formation of the CCDC137-LZTS2-β-TrCP complex, promoting HCC progression.
Fig. 6: Inhibitory peptides targeting the CCDC137-LZTS2-β-TrCP complex attenuate β-catenin and AKT activation in HCC.
Fig. 7: Inhibition of HCC progression by peptides targeting the CCDC137 and LZTS2 interaction.
Fig. 8: CCDC137 and LZTS2 exhibited a negative correlation in HCC tissues.

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Data availability

The data supporting the findings of this study are available upon reasonable request to the corresponding author.

References

  1. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Article  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  3. Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr BS, Baron RL. Extrahepatic metastases of hepatocellular carcinoma. Radiology. 2000;216:698–703.

    Article  CAS  PubMed  Google Scholar 

  4. Furuta M, Ueno M, Fujimoto A, Hayami S, Yasukawa S, Kojima F, et al. Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors. J Hepatol. 2017;66:363–73.

    Article  CAS  PubMed  Google Scholar 

  5. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.

    Article  CAS  PubMed  Google Scholar 

  6. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203–22.

    Article  PubMed  Google Scholar 

  7. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell. 2023;186:1564–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–8.

    Article  CAS  PubMed  Google Scholar 

  10. Jiang WG, Sanders AJ, Katoh M, Ungefroren H, Gieseler F, Prince M, et al. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin Cancer Biol. 2015;35:S244–S275.

    Article  PubMed  Google Scholar 

  11. Dimri M, Humphries A, Laknaur A, Elattar S, Lee TJ, Sharma A, et al. NAD(P)H Quinone dehydrogenase 1 ablation inhibits activation of the phosphoinositide 3-kinase/akt serine/threonine kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways and blocks metabolic adaptation in hepatocellular carcinoma. Hepatology. 2020;71:549–68.

    Article  CAS  PubMed  Google Scholar 

  12. Zuo Q, He J, Zhang S, Wang H, Jin G, Jin H, et al. PPARgamma coactivator-1alpha suppresses metastasis of hepatocellular carcinoma by inhibiting Warburg effect by PPARgamma-dependent WNT/beta-catenin/pyruvate dehydrogenase kinase isozyme 1 axis. Hepatology. 2021;73:644–60.

    Article  CAS  PubMed  Google Scholar 

  13. Loesch R, Caruso S, Paradis V, Godard C, Gougelet A, Renault G, et al. Deleting the beta-catenin degradation ___domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth. J Hepatol. 2022;77:424–35.

    Article  CAS  PubMed  Google Scholar 

  14. Baik SH, Lee J, Lee YS, Jang JY, Kim CW. ANT2 shRNA downregulates miR-19a and miR-96 through the PI3K/Akt pathway and suppresses tumor growth in hepatocellular carcinoma cells. Exp Mol Med. 2016;48:e222.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu Z, Yan W, Liu S, Liu Z, Xu P, Fang W. Regulatory network and targeted interventions for CCDC family in tumor pathogenesis. Cancer Lett. 2023;565:216225.

    Article  CAS  PubMed  Google Scholar 

  17. Guo L, Li B, Lu Z, Liang H, Yang H, Chen Y, et al. CCDC137 is a prognostic biomarker and correlates with immunosuppressive tumor microenvironment based on pan-cancer analysis. Front Mol Biosci. 2021;8:674863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dai W, Wu J, Peng X, Hou W, Huang H, Cheng Q, et al. CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer. Clin Transl Med. 2022;12:e1087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tao S, Xie SJ, Diao LT, Lv G, Hou YR, Hu YX, et al. RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization. J Exp Clin Cancer Res. 2023;42:194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lu Y, Li X, Liu H, Xue J, Zeng Z, Dong X, et al. beta-Trcp and CK1delta-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma. Oncogene. 2021;40:1269–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hu X, Zhao Y, Wei L, Zhu B, Song D, Wang J, et al. CCDC178 promotes hepatocellular carcinoma metastasis through modulation of anoikis. Oncogene. 2017;36:4047–59.

    Article  CAS  PubMed  Google Scholar 

  22. Cheng X, Wang Y, Gong Y, Li F, Guo Y, Hu S, et al. Structural basis of FYCO1 and MAP1LC3A interaction reveals a novel binding mode for Atg8-family proteins. Autophagy. 2016;12:1330–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang H, Zhang CZ, Lu SX, Zhang MF, Liu LL, Luo RZ, et al. A coiled-coil ___domain containing 50 splice variant is modulated by serine/arginine-rich splicing factor 3 and promotes hepatocellular carcinoma in mice by the ras signaling pathway. Hepatology. 2019;69:179–95.

    Article  CAS  PubMed  Google Scholar 

  24. Cabeza-Arvelaiz Y, Thompson TC, Sepulveda JL, Chinault AC. LAPSER1: a novel candidate tumor suppressor gene from 10q24.3. Oncogene. 2001;20:6707–17.

    Article  CAS  PubMed  Google Scholar 

  25. Thyssen G, Li TH, Lehmann L, Zhuo M, Sharma M, Sun Z. LZTS2 is a novel beta-catenin-interacting protein and regulates the nuclear export of beta-catenin. Mol Cell Biol. 2006;26:8857–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xu S, Li Y, Lu Y, Huang J, Ren J, Zhang S, et al. LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85. Cancer Lett. 2018;420:38–48.

    Article  CAS  PubMed  Google Scholar 

  27. Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, et al. TRIB3 interacts with beta-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology. 2019;156:708–721 e715.

    Article  CAS  PubMed  Google Scholar 

  28. Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. beta-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022;132:e154515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Q, Chen X, Hay N. Akt as a target for cancer therapy: more is not always better (lessons from studies in mice). Br J Cancer. 2017;117:159–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rogel A, Willoughby JE, Buchan SL, Leonard HJ, Thirdborough SM, Al-Shamkhani A. Akt signaling is critical for memory CD8(+) T-cell development and tumor immune surveillance. Proc Natl Acad Sci USA. 2017;114:E1178–E1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ruiz de Galarreta M, Bresnahan E, Molina-Sanchez P, Lindblad KE, Maier B, Sia D, et al. beta-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019;9:1124–41.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We express our gratitude to Wang Guangxin from the Institute of Hydrobiology, Chinese Academy of Sciences, for providing technical support in confocal microscopy imaging. Additionally, we extend our thanks to Professor Li Yan from Zhongnan Hospital of Wuhan University, Wuhan, China, for generously supplying HCCLM9 cells.

Funding

This work was supported by the National Natural Science Foundation of China (82372994, 82003003, 81874189), Wuhan Science and Technology Bureau 2022 annual key research and development project (2022023502015182), 2021 Wuhan Young and Middle-aged Medical Backbone Talent Training Project (2021ZQNYX008).

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  1. These authors contributed equally: Lei Xu, Qiumeng Liu, Hailing Liu.

Authors and Affiliations

  1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    Lei Xu, Qiumeng Liu, Hailing Liu, Feimu Fan, Pengcheng Li, Shiwei Yue, Jie Mo, Zhicheng Liu, Renshun Dong, Xuewu Zhang, Hanhua Dong, Huifang Liang, Xiaoping Chen, Bixiang Zhang, Lin Chen & Jin Chen

  2. Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan, Hubei, China

    Lei Xu, Qiumeng Liu, Hailing Liu, Feimu Fan, Pengcheng Li, Shiwei Yue, Jie Mo, Zhicheng Liu, Renshun Dong, Xuewu Zhang, Hanhua Dong, Huifang Liang, Xiaoping Chen, Bixiang Zhang, Lin Chen & Jin Chen

  3. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, China

    Lei Xu, Qiumeng Liu, Hailing Liu, Feimu Fan, Pengcheng Li, Shiwei Yue, Jie Mo, Zhicheng Liu, Renshun Dong, Xuewu Zhang, Hanhua Dong, Huifang Liang, Xiaoping Chen, Bixiang Zhang, Lin Chen & Jin Chen

  4. Key Laboratory of Organ Transplantation, Ministry of Education; Key Laboratory of Organ Transplantation, National Health Commission; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China

    Xiaoping Chen & Bixiang Zhang

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Contributions

Jin Chen and Bixiang Zhang conceived and designed the study. Lei Xu, Qiumeng Liu and Hailing Liu performed the experiments. Shiwei Yue, Feimu Fan, Pengcheng Li and Jie Mo collected the clinical specimens and data. Zhicheng Liu, Renshun Dong and Xuewu Zhang performed the statistical analysis. Lei Xu drafted the manuscript. Hanhua Dong, Huifang Liang, Lin Chen, Bixiang Zhang and Jin Chen contributed to the critical revision of the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Bixiang Zhang, Lin Chen or Jin Chen.

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The authors declare no competing interests.

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The utilization of human tissue samples in this study has been approved by the Ethics Committee of Tongji Hospital, and informed consent exemption was approved by the institutional ethics committee (TJ-IRB20211163). All animal experiments involved in this study were approved by the Ethics Committee of Tongji Hospital (TJ-202304015).

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Xu, L., Liu, Q., Liu, H. et al. Disrupting CCDC137-mediated LZTS2 and β-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via β-catenin and AKT. Cell Death Differ 32, 134–148 (2025). https://doi.org/10.1038/s41418-024-01328-z

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