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Kaida A, Yamamoto S, Parrales A, et al. DNAJA1 promotes cancer metastasis through interaction with mutant p53. Oncogene. 2021;40(31):5013-5025doi: 10.1038/s41388-021-01921-3.
Kaida, A., Yamamoto, S., Parrales, A., Young, E. D., Ranjan, A., Alalem, M. A., Morita, K. I., Oikawa, Y., Harada, H., Ikeda, T., Thomas, S. M., Diaz, F. J., & Iwakuma, T. (2021). DNAJA1 promotes cancer metastasis through interaction with mutant p53. Oncogene, 40(31), 5013-5025. https://doi.org/10.1038/s41388-021-01921-3
Kaida, Atsushi, et al. "DNAJA1 promotes cancer metastasis through interaction with mutant p53." Oncogene vol. 40,31 (2021): 5013-5025. doi: https://doi.org/10.1038/s41388-021-01921-3
Kaida A, Yamamoto S, Parrales A, Young ED, Ranjan A, Alalem MA, Morita KI, Oikawa Y, Harada H, Ikeda T, Thomas SM, Diaz FJ, Iwakuma T. DNAJA1 promotes cancer metastasis through interaction with mutant p53. Oncogene. 2021 Aug;40(31):5013-5025. doi: 10.1038/s41388-021-01921-3. Epub 2021 Jun 28. PMID: 34183772.
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Oncogene. 2021 Aug;40(31):5013-5025. doi: 10.1038/s41388-021-01921-3. Epub 2021 Jun 28.

DNAJA1 promotes cancer metastasis through interaction with mutant p53.

Oncogene

Atsushi Kaida, Satomi Yamamoto, Alejandro Parrales, Eric D Young, Atul Ranjan, Mohamed A Alalem, Kei-Ichi Morita, Yu Oikawa, Hiroyuki Harada, Tohru Ikeda, Sufi M Thomas, Francisco J Diaz, Tomoo Iwakuma

Affiliations

  1. Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA.
  2. Department of Oral Radiation Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  3. Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA.
  4. Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo, Japan.
  5. Bioresource Research Center, Tokyo, Japan.
  6. Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo, Japan.
  7. Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  8. Department of Otolaryngology, Head and Neck Surgery, Kansas, KS, USA.
  9. Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas, KS, USA.
  10. Department of Cancer Biology, University of Kansas Medical Center, Kansas, KS, USA. [email protected].
  11. Department of Pediatrics, Children's Mercy Research Institute, Kansas, MO, USA. [email protected].

PMID: 34183772 DOI: 10.1038/s41388-021-01921-3

Abstract

Accumulation of mutant p53 (mutp53) is crucial for its oncogenic gain of function activity. DNAJA1, a member of J-domain containing proteins or heat shock protein 40, is shown to prevent unfolded mutp53 from proteasomal degradation. However, the biological function of DNAJA1 remains largely unknown. Here we show that DNAJA1 promotes tumor metastasis by accumulating unfolded mutp53. Levels of DNAJA1 in head and neck squamous cell carcinoma (HNSCC) tissues were higher than those in normal tissues. Knockdown of DNAJA1 in HNSCC cell lines carrying unfolded mutp53 significantly decreased the levels of mutp53, filopodia/lamellipodia formation, migratory potential, and active forms of CDC42/RAC1, which were not observed in HNSCC cells with DNA contact mutp53, wild-type p53, or p53 null. Such mutp53-dependent functions of DNAJA1 were supported by the observation that DNAJA1 selectively bound to unfolded mutp53. Moreover, DNAJA1 knockdown in HNSCC cells carrying unfolded mutp53 inhibited primary tumor growth and metastases to the lymph nodes and lungs. Our study suggests that DNAJA1 promotes HNSCC metastasis mainly in a manner dependent on mutp53 status, suggesting DNAJA1 as a potential therapeutic target for HNSCC harboring unfolded mutp53.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

References

  1. Cyr DM, Ramos CH. Specification of Hsp70 function by type I and type II Hsp40. Subcell Biochem. 2015;78:91–102. - PubMed
  2. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature. 2011;475:324–32. - PubMed
  3. Large AT, Goldberg MD, Lund PA. Chaperones and protein folding in the archaea. Biochem Soc Trans. 2009;37:46–51. - PubMed
  4. Kampinga HH, Craig EA. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol. 2010;11:579–92. - PubMed
  5. Chen CY, Jan CI, Lo JF, Yang SC, Chang YL, Pan SH, et al. Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation. Cancer Res. 2013;73:4009–19. - PubMed
  6. Chen CY, Chiou SH, Huang CY, Jan CI, Lin SC, Hu WY, et al. Tid1 functions as a tumour suppressor in head and neck squamous cell carcinoma. J Pathol. 2009;219:347–55. - PubMed
  7. Liu T, Jiang W, Han D, Yu L. DNAJC25 is downregulated in hepatocellular carcinoma and is a novel tumor suppressor gene. Oncol Lett. 2012;4:1274–80. - PubMed
  8. Chen KY, Huang YH, Teo WH, Chang CW, Chen YS, Yeh YC et al. Loss of Tid1/DNAJA3 co-chaperone promotes progression and recurrence of hepatocellular carcinoma after surgical resection: a novel model to stratify risk of recurrence. Cancers. 2021; 13. - PubMed
  9. Xu D, Tong X, Sun L, Li H, Jones RD, Liao J, et al. Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53. Mol Carcinog. 2019;58:2052–64. - PubMed
  10. Yang S, Ren X, Liang Y, Yan Y, Zhou Y, Hu J, et al. KNK437 restricts the growth and metastasis of colorectal cancer via targeting DNAJA1/CDC45 axis. Oncogene. 2020;39:249–61. - PubMed
  11. Nishizawa S, Hirohashi Y, Torigoe T, Takahashi A, Tamura Y, Mori T, et al. HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells. Cancer Res. 2012;72:2844–54. - PubMed
  12. Yang T, Li XN, Li XG, Li M, Gao PZ. DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial-mesenchymal transition. Biochem Biophys Res Commun. 2014;455:298–304. - PubMed
  13. He HL, Lee YE, Chen HP, Hsing CH, Chang IW, Shiue YL, et al. Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Exp Mol Pathol. 2015;98:338–45. - PubMed
  14. Uno Y, Kanda M, Miwa T, Umeda S, Tanaka H, Tanaka C, et al. Increased expression of DNAJC12 is associated with aggressive phenotype of gastric cancer. Ann Surg Oncol. 2019;26:836–44. - PubMed
  15. Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148:244–58. - PubMed
  16. Walerych D, Lisek K, Del, Sal G. Mutant p53: one, no one, and one hundred thousand. Front Oncol. 2015;5:289. - PubMed
  17. Parrales A, Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy. Front Oncol. 2015;5:288. - PubMed
  18. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357:2552–61. - PubMed
  19. Zhou G, Liu Z, Myers JN. TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. J Cell Biochem. 2016;117:2682–92. - PubMed
  20. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev. 2008;22:1337–44. - PubMed
  21. Mantovani F, Collavin L, Del, Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212. - PubMed
  22. Parrales A, Ranjan A, Iyer SV, Padhye S, Weir SJ, Roy A, et al. DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol. 2016;18:1233–43. - PubMed
  23. Chen JS, Coustan-Smith E, Suzuki T, Neale GA, Mihara K, Pui CH, et al. Identification of novel markers for monitoring minimal residual disease in acute lymphoblastic leukemia. Blood. 2001;97:2115–20. - PubMed
  24. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008. - PubMed
  25. Peltonen JK, Helppi HM, Paakko P, Turpeenniemi-Hujanen T, Vahakangas KH. p53 in head and neck cancer: functional consequences and environmental implications of TP53 mutations. Head Neck Oncol. 2010;2:36. - PubMed
  26. Mattila PK, Lappalainen P. Filopodia: molecular architecture and cellular functions. Nat Rev Mol Cell Biol. 2008;9:446–54. - PubMed
  27. Ridley AJ. Life at the leading edge. Cell. 2011;145:1012–22. - PubMed
  28. Iyer SV, Parrales A, Begani P, Narkar A, Adhikari AS, Martinez LA, et al. Allele-specific silencing of mutant p53 attenuates dominant-negative and gain-of-function activities. Oncotarget. 2016;7:5401–15. - PubMed
  29. Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell. 1995;81:53–62. - PubMed
  30. Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 2014;16:357–66. - PubMed
  31. Parrales A, McDonald P, Ottomeyer M, Roy A, Shoenen FJ, Broward M, et al. Comparative oncology approach to drug repurposing in osteosarcoma. PLoS ONE. 2018;13:e0194224. - PubMed
  32. Sakabe M, Fan J, Odaka Y, Liu N, Hassan A, Duan X, et al. YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proc Natl Acad Sci USA. 2017;114:10918–23. - PubMed
  33. Escoll M, Gargini R, Cuadrado A, Anton IM, Wandosell F. Mutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ. Oncogene. 2017;36:3515–27. - PubMed
  34. Gannon JV, Greaves R, Iggo R, Lane DP. Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific for the mutant form. EMBO J. 1990;9:1595–602. - PubMed
  35. Vojtesek B, Dolezalova H, Lauerova L, Svitakova M, Havlis P, Kovarik J, et al. Conformational changes in p53 analysed using new antibodies to the core DNA binding domain of the protein. Oncogene. 1995;10:389–93. - PubMed
  36. Parrales A, Thoenen E, Iwakuma T. The interplay between mutant p53 and the mevalonate pathway. Cell Death Differ. 2018;25:460–70. - PubMed
  37. Yue X, Zhang C, Zhao Y, Liu J, Lin AW, Tan VM, et al. Gain-of-function mutant p53 activates small GTPase Rac1 through SUMOylation to promote tumor progression. Genes Dev. 2017;31:1641–54. - PubMed
  38. Ergulen E, Becsi B, Csomos I, Fesus L, Kanchan K. Identification of DNAJA1 as a novel interacting partner and a substrate of human transglutaminase 2. Biochem J. 2016;473:3889–901. - PubMed
  39. Tracz-Gaszewska Z, Klimczak M, Biecek P, Herok M, Kosinski M, Olszewski MB, et al. Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation. Oncotarget. 2017;8:82123–43. - PubMed
  40. Ahn BY, Trinh DL, Zajchowski LD, Lee B, Elwi AN, Kim SW. Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer. Oncogene. 2010;29:1155–66. - PubMed

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