DNAJA1 promotes cancer metastasis through interaction with mutant p53.
DNAJA1 promotes cancer metastasis through interaction with mutant p53.
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DOI：
10.1038/s41388-021-01921-3
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发表时间：
2021-08
期刊：
影响因子：
8
通讯作者：
Iwakuma T
中科院分区：
文献类型：
--
作者：
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
突变型p53（mutp 53）的积累对于其致癌功能活性的获得至关重要。DNAJA 1是含J结构域的蛋白或热休克蛋白40的成员，显示出防止未折叠的mutp 53被蛋白酶体降解。然而，DNAJA 1的生物学功能在很大程度上仍然未知。在这里，我们表明，DNAJA 1通过积累未折叠的mutp 53促进肿瘤转移。DNAJA 1在头颈部鳞癌组织中的表达高于正常组织。在携带未折叠mutp 53的HNSCC细胞系中敲低DNAJA 1显著降低了mutp 53的水平、丝状伪足/板状伪足形成、迁移潜力和CDC 42/RAC 1的活性形式，而在DNA接触mutp 53、野生型p53或p53缺失的HNSCC细胞中未观察到这些。DNAJA 1选择性结合未折叠的mutp 53的观察结果支持了DNAJA 1的这种mutp 53依赖性功能。此外，在携带未折叠mutp 53的HNSCC细胞中敲低DNAJA 1抑制原发性肿瘤生长和向淋巴结和肺的转移。我们的研究表明，DNAJA 1主要以依赖于mutp 53状态的方式促进HNSCC转移，这表明DNAJA 1是携带未折叠mutp 53的HNSCC的潜在治疗靶点。
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.
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