转移
癌症研究
生物
上皮-间质转换
癌症
下调和上调
肿瘤进展
细胞
基因
生物化学
遗传学
作者
Jiayi Zhang,Zihui Ni,Yu Zhang,Yan Guo,Rundong Zhai,Meng Qi Wang,Zizhen Gong,Mengyao Wang,Fanxu Zeng,Ziyue Gu,Qianming Chen,Laikui Liu,Zhiyong Wang,Weiwen Zhu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-08-09
标识
DOI:10.1158/0008-5472.can-24-0067
摘要
Abstract Tumor invasion and metastasis are the underlying causes of the high mortality rate of oral squamous cell carcinoma (OSCC). Energy metabolism reprogramming has been identified as a crucial process mediating tumor metastasis, thus indicating an urgent need for in-depth investigation of the specific mechanisms of tumor energy metabolism. Here, we identified an RNA-binding protein, DAZ associated protein 1 (DAZAP1), as a tumor-promoting factor with an important role in OSCC progression. DAZAP1 was significantly upregulated in OSCC, which enhanced the migration and invasion of OSCC cells and induced the epithelial-mesenchymal transition (EMT). RNA-seq analysis and experimental validation demonstrated that DAZAP1 regulates mitochondrial energy metabolism in OSCC. Mechanistically, DAZAP1 underwent liquid-liquid phase separation (LLPS) to accumulate in the nucleus where it enhanced cytochrome-c oxidase 16 (COX16) expression by regulating pre-mRNA alternative splicing, thereby promoting OSCC invasion and mitochondrial respiration. In mouse OSCC models, loss of DAZAP1 suppressed EMT, downregulated COX16, and reduced tumor growth and metastasis. In OSCC patient samples, expression of DAZAP1 positively correlated with COX16, and high expression of both proteins was associated with poor patient prognosis. Together, these findings revealed a mechanism by which DAZAP1 supports mitochondrial metabolism and tumor development of OSCC, suggesting the potential of therapeutic strategies targeting DAZAP1 to block OSCC invasion and metastasis.
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