DNAJA1 promotes cancer metastasis through interaction with mutant p53

• Published in: Oncogene 2021-08, Vol.40 (31), p.5013-5025
• Main Authors: Kaida, Atsushi, Yamamoto, Satomi, Parrales, Alejandro, Young, Eric D., Ranjan, Atul, Alalem, Mohamed A., Morita, Kei-ichi, Oikawa, Yu, Harada, Hiroyuki, Ikeda, Tohru, Thomas, Sufi M., Diaz, Francisco j., Iwakuma, Tomoo
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 42/89; 631/67/1536/1665; 631/67/322; 64/60; 692/53/2422; 82/80; 96/44; Animals; Apoptosis; Biomarkers, Tumor; Cancer; cdc42 GTP-Binding Protein - metabolism; Cdc42 protein; Cell Biology; Development and progression; Disease Models, Animal; Disease Progression; Disease Susceptibility; Filopodia; Gene Expression; Gene Knockdown Techniques; Gene mutations; Genetic aspects; Head & neck cancer; Heat shock proteins; Heterografts; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Human Genetics; Humans; Internal Medicine; Lamellipodia; Lymph nodes; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutants; Neoplasm Metastasis; Neoplasm Staging; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncogenes - genetics; Oncology; Oncology, Experimental; p53 Protein; Proteasomes; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Squamous cell carcinoma; Therapeutic targets; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Unfolded Protein Response - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01921-3

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.