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ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer

  • Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Constant DNA damage occurs in cells, and the cells are programmed to respond constitutively. This study explored the roles of ataxia-telangiectasia mutated interactor (ATMIN), one of the impaired pathways involving the DNA damage response (DDR) in mismatch repair-deficient [microsatellite instability (MSI)-high] colorectal carcinoma (CRC).

Methods

Expression of ATMIN messenger RNA (mRNA) was detected in CRC specimens with microsatellite instability (MSI) characteristics. The effects of ectopic ATMIN expression and ATMIN knockdown on invasion abilities were evaluated in MSI-high cell lines, and liver metastasis ability was investigated in vivo. Protein-protein interactions were assessed by coimmunoprecipitation analyses in vitro.

Results

Decreased ATMIN expression was positively correlated with advanced stage of disease (P < 0.05), lymph node metastases (P < 0.05), and deeper invasion (P < 0.05) in MSI-high tumors. Transient or stable ATMIN knockdown significantly increased cell motility. Moreover, in the high-throughput microarray and gene set enrichment analysis, ATMIN was shown to act on the Wnt-signaling pathway via PARP1. This cascade influences β-catenin/transcription factor 4 (TCF4) binding affinity in MSI-high tumors, and PARP1 inhibition significantly decreased the number of metastases from ATMIN knockdown cancer cells.

Conclusions

The results not only indicated the critical role of ATMIN, but also shed new light on PARP1 inhibitors, providing a basis for further clinical trials of MSI-high CRC.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics. CA Cancer J Clin. 2009;59:225–49.

    Article  PubMed  Google Scholar 

  2. Lin BR, Chang CC, Chen RJ, et al. Connective tissue growth factor acts as a therapeutic agent and predictor for peritoneal carcinomatosis of colorectal cancer. Clin Cancer Res. 2011;17:3077–88.

    Article  CAS  PubMed  Google Scholar 

  3. Lin BR, Chang CC, Che TF, et al. Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology. 2005;128:9–23.

    Article  CAS  PubMed  Google Scholar 

  4. Manfredi S, Bouvier AM, Lepage C, Hatem C, Dancourt V, Faivre J. Incidence and patterns of recurrence after resection for cure of colonic cancer in a well-defined population. Br J Surg. 2006;93:1115–22.

    Article  CAS  PubMed  Google Scholar 

  5. Lin BR, Huang MT, Chen ST, et al. Prognostic significance of TWEAK expression in colorectal cancer and effect of its inhibition on invasion. Ann Surg Oncol. 2012;19(Suppl 3):S385–94.

    Article  PubMed  Google Scholar 

  6. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145:148–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Soreide K, Janssen EA, Soiland H, Korner H, Baak JP. Microsatellite instability in colorectal cancer. Br J Surg. 2006;93:395–406.

    Article  CAS  PubMed  Google Scholar 

  8. Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100:266–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28:3219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pilie PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McNees CJ, Conlan LA, Tenis N, Heierhorst J. ASCIZ regulates lesion-specific Rad51 focus formation and apoptosis after methylating DNA damage. EMBO J. 2005;24:2447–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jurado S, Smyth I, van Denderen B, et al. Dual functions of ASCIZ in the DNA base damage response and pulmonary organogenesis. PLoS Genet. 2010;6:e1001170.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Chavan SD, Shetty NL, Kanuri M. Comparative evaluation of garlic extract mouthwash and chlorhexidine mouthwash on salivary Streptococcus mutans count: an in vitro study. Oral Health Prev Dent. 2010;8:369–74.

    PubMed  Google Scholar 

  15. Kanu N, Behrens A. ATMIN defines an NBS1-independent pathway of ATM signalling. EMBO J. 2007;26:2933–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Loizou JI, Sancho R, Kanu N, et al. ATMIN is required for maintenance of genomic stability and suppression of B cell lymphoma. Cancer Cell. 2011;19:587–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu X, Zha S. ATMIN: a new tumor suppressor in developing B cells. Cancer Cell. 2011;19:569–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kanu N, Penicud K, Hristova M, et al. The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. J Biol Chem. 2010;285:38534–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Heierhorst J. Mdt1/ASCIZ: a new DNA damage response protein family. Cell Cycle. 2008;7:2654–60.

    Article  CAS  PubMed  Google Scholar 

  20. Jurado S, Gleeson K, O’Donnell K, et al. The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. J Exp Med. 2012;209:1629–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li YJ, Lai WT, Chang CC, et al. Ataxia-telangiectasia mutated interactor regulates head and neck cancer metastasis via KRas expression. Oral Oncol. 2017;66:100–7.

    Article  CAS  PubMed  Google Scholar 

  22. Pino MS, Chung DC. Microsatellite instability in the management of colorectal cancer. Exp Rev Gastroenterol Hepatol. 2011;5:385–99.

    Article  Google Scholar 

  23. Morikawa K, Walker SM, Jessup JM, Fidler IJ. In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res. 1988;48:1943–8.

    CAS  PubMed  Google Scholar 

  24. Mir R, Pradhan SJ, Patil P, Mulherkar R, Galande S. Wnt/beta-catenin signaling regulated SATB1 promotes colorectal cancer tumorigenesis and progression. Oncogene. 2016;35:1679–91.

    Article  CAS  PubMed  Google Scholar 

  25. Shitashige M, Hirohashi S, Yamada T. Wnt-signaling inside the nucleus. Cancer Sci. 2008;99:631–7.

    Article  CAS  PubMed  Google Scholar 

  26. Li CG, Mahon C, Sweeney NM, et al. PPARgamma interaction with UBR5/ATMIN promotes DNA repair to maintain endothelial homeostasis. Cell Rep. 2019;26:1333–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jurado S, Conlan LA, Baker EK, et al. ATM substrate Chk2-interacting Zn2+ finger (ASCIZ) is a bi-functional transcriptional activator and feedback sensor in the regulation of dynein light chain (DYNLL1) expression. J Biol Chem. 2012;287:3156–64.

    Article  CAS  PubMed  Google Scholar 

  28. Goggolidou P, Stevens JL, Agueci F, et al. ATMIN is a transcriptional regulator of both lung morphogenesis and ciliogenesis. Development. 2014;141:3966–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang T, Cronshaw J, Kanu N, Snijders AP, Behrens A. UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function. Proc Natl Acad Sci U S A. 2014;111:12091–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Haince JF, McDonald D, Rodrigue A, et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem. 2008;283:1197–208.

    Article  CAS  PubMed  Google Scholar 

  31. Haince JF, Kozlov S, Dawson VL, et al. Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem. 2007;282:16441–53.

    Article  CAS  PubMed  Google Scholar 

  32. Aguilar-Quesada R, Munoz-Gamez JA, Martin-Oliva D, et al. Interaction between ATM and PARP-1 in response to DNA damage and sensitization of ATM deficient cells through PARP inhibition. BMC Mol Biol. 2007;8:29.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: “PAR-laying” NAD+ into a nuclear signal. Genes Dev. 2005;19:1951–67.

    Article  CAS  PubMed  Google Scholar 

  34. Ali AAE, Timinszky G, Arribas-Bosacoma R, et al. The zinc-finger domains of PARP1 cooperate to recognize DNA strand breaks. Nat Struct Mol Biol. 2012;19:685–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Langelier MF, Pascal JM. PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Curr Opin Struct Biol. 2013;23:134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Polo SE, Jackson SP. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 2011;25:409–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sukhanova MV, Abrakhi S, Joshi V, et al. Single-molecule detection of PARP1 and PARP2 interaction with DNA strand breaks and their poly(ADP-ribosyl)ation using high-resolution AFM imaging. Nucl Acids Res. 2016;44:e60.

    Article  PubMed  Google Scholar 

  38. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28:3380–7.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Noordermeer SM, Adam S, Setiaputra D, et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature. 2018;560:117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Becker JR, Cuella-Martin R, Barazas M, et al. The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat Commun. 2018;9:5406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grube K, Burkle A. Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Natl Acad Sci U S A. 1992;89:11759–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gourley C, Balmana J, Ledermann A, et al. Moving from poly (ADP-Ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. J Clin Oncol. 2019;37:2257.

    Article  CAS  PubMed  Google Scholar 

  43. Javle M, Shacham-Shmueli E, Xiao L, et al. Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 phase 2 nonrandomized clinical trials. JAMA Oncol. 2021;7(5):693–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from National Taiwan University Hospital (NTUH.108-S4318) and Taiwan Health Foundation.

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Authors and Affiliations

  1. Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan

    Yue-Ju Li PhD, Cheng-Ning Yang PhD, Mark Yen-Ping Kuo PhD, Wei-Ting Lai PhD & Tai-Sheng Wu PhD

  2. Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

    Yue-Ju Li PhD & Been-Ren Lin MD, PhD

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  1. Yue-Ju Li PhD
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Correspondence to Been-Ren Lin MD, PhD.

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Li, YJ., Yang, CN., Kuo, M.YP. et al. ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer. Ann Surg Oncol 28, 8544–8554 (2021). https://doi.org/10.1245/s10434-021-10322-5

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  • DOI: https://doi.org/10.1245/s10434-021-10322-5

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