Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University (Ningbo Yinzhou People's Hospital), 251, Baizhang Road, Ningbo, Zhejiang, 315040, People's Republic of China.
Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang, 322000, People's Republic of China.
J Exp Clin Cancer Res. 2024 Jan 2;43(1):3. doi: 10.1186/s13046-023-02936-2.
Lung cancer is a malignant tumor with the highest mortality worldwide. Abnormalities in the ubiquitin proteasome system are considered to be contributed to lung cancer progression with deleterious effects. DDB1 and CUL4 associated factor 13 (DCAF13) is a substrate receptor of the E3 ubiquitin ligase CRL4, but its role in lung cancer remains unknown. In this study, we aimed to investigate the regulatory mechanisms of DCAF13 in lung adenocarcinoma (LUAD).
So as to investigate the effect of DCAF13 on lung adenocarcinoma cell function using in vivo and in vitro. Mechanistically, we have identified the downstream targets of DCAF13 by using RNA-sequencing, as well as ubiquitination assays, co-immunoprecipitation, immunofluorescence, immunohistochemistry and chromatin immunoprecipitation - qPCR experiments.
Our findings reveal that DCAF13 is a carcinogenic factor in LUAD, as it is highly expressed and negatively correlated with clinical outcomes in LUAD patients. Through RNA-sequencing, it has been shown that DCAF13 negatively regulates the p53 signaling pathway and inhibits p53 downstream targets including p21, BAX, FAS, and PIDD1. We also demonstrate that DCAF13 can bind to p53 protein, leading to K48-linked ubiquitination and degradation of p53. Functionally, we have shown that DCAF13 knockdown inhibits cell proliferation and migration. Our results highlight the significant role of DCAF13 in promoting LUAD progression by inhibiting p53 protein stabilization and the p53 signaling pathway. Furthermore, our findings suggest that high DCAF13 expression is a poor prognostic indicator in LUAD, and DCAF13 may be a potential therapeutic target for treating with this aggressive cancer.
The DCAF13 as a novel negative regulator of p53 to promote LUAD progression via facilitating p53 ubiquitination and degradation, suggesting that DCAF13 might be a novel biomarker and therapeutical target for LUAD.
肺癌是全球死亡率最高的恶性肿瘤。泛素蛋白酶体系统的异常被认为与肺癌的进展有关，具有有害作用。DDB1 和 CUL4 相关因子 13（DCAF13）是 E3 泛素连接酶 CRL4 的底物受体，但它在肺癌中的作用尚不清楚。在这项研究中，我们旨在研究 DCAF13 在肺腺癌（LUAD）中的调节机制。
为了研究 DCAF13 对肺腺癌细胞功能的影响，我们采用了体内和体外实验。从机制上，我们通过 RNA 测序、泛素化实验、共免疫沉淀、免疫荧光、免疫组化和染色质免疫沉淀 - qPCR 实验确定了 DCAF13 的下游靶标。
我们的研究结果表明，DCAF13 是 LUAD 的致癌因素，因为它在 LUAD 患者中高表达且与临床结局呈负相关。通过 RNA 测序，我们发现 DCAF13 负调控 p53 信号通路，并抑制 p53 下游靶标，包括 p21、BAX、FAS 和 PIDD1。我们还证明 DCAF13 可以与 p53 蛋白结合，导致 p53 蛋白 K48 连接的泛素化和降解。在功能上，我们发现 DCAF13 敲低抑制细胞增殖和迁移。我们的研究结果强调了 DCAF13 通过抑制 p53 蛋白稳定和 p53 信号通路促进 LUAD 进展的重要作用。此外，我们的研究结果表明，高 DCAF13 表达是 LUAD 的不良预后指标，DCAF13 可能是治疗这种侵袭性癌症的潜在治疗靶点。
DCAF13 作为 p53 的新型负调控因子，通过促进 p53 泛素化和降解来促进 LUAD 的进展，提示 DCAF13 可能是 LUAD 的新型生物标志物和治疗靶点。
