The FBXW7-binding sites on FAM83D are potential targets for cancer therapy

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-03-07 DOI:10.1186/s13058-024-01795-9
Xiaoyu Jiang, Yuli Wang, Lulu Guo, Yige Wang, Tianshu Miao, Lijuan Ma, Qin Wei, Xiaoyan Lin, Jian-Hua Mao, Pengju Zhang
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Abstract

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.
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FAM83D 上的 FBXW7 结合位点是癌症治疗的潜在靶点
越来越多的证据表明,FAM83D在人类癌症中具有致癌功能,但FAM83D如何发挥其致癌功能在很大程度上仍不清楚。在此,我们研究了FAM83D/FBXW7相互作用在乳腺癌(BC)中的重要性。我们通过全面的突变分析和共沉淀实验系统地绘制了FAM83D上的FBXW7结合位点。FAM83D上的FBXW7结合位点突变导致FAM83D失去了促进FBXW7泛素化和蛋白酶体降解的能力;失去了体外促进细胞增殖、迁移和侵袭的能力;失去了体内促进肿瘤生长和转移的能力,这表明FAM83D上的FBXW7结合位点对其致癌功能至关重要。对 FAM83D 的荟萃评估显示,FAM83D 对预后的影响与分子亚型无关。FAM83D表达越高,预后越差。此外,FAM83D的高表达会使BC对化疗产生耐药性,这在体外实验中得到了验证。我们的结论是,FAM83D上FBXW7结合位点的鉴定不仅揭示了FAM83D致癌功能的重要性,还为药物靶向提供了有价值的见解。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
0.00%
发文量
76
期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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