Department of Medicine and Life Sciences, Universidad Pompeu Fabra, Barcelona, 08003, Spain.
Thoracic Cancers Translational Genomics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, 08035, Spain.
J Exp Clin Cancer Res. 2024 Apr 29;43(1):127. doi: 10.1186/s13046-024-03045-4.
TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers.
Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through in vitro and in vivo experiments, we explored proliferation, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis.
Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability.
Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.
TP53 是人类癌症中最常发生突变的基因，它调控着一个复杂的转录程序，对癌症的预防至关重要。虽然某些依赖 TP53 的基因已经得到了广泛的研究，但其他基因，如最近发现的 RNF144B，仍然知之甚少。这种 E3 泛素连接酶在鼠 Eμ Myc 驱动的淋巴瘤中显示出强大的肿瘤抑制活性，强调了它在 TP53 网络中的重要性。然而，关于其靶点及其在癌症发展中的作用知之甚少，需要进一步探索。在这项工作中，我们研究了 RNF144B 在人类癌症中非造血细胞中除了造血细胞以外的肿瘤抑制作用。
我们利用 TP53 野生型细胞，在人类和鼠源性非转化和癌变细胞中生成了缺乏 RNF144B 的模型。通过蛋白质组学、转录组学和功能分析，我们评估了 RNF144B 对细胞增殖和转化的影响。通过体外和体内实验，我们研究了增殖、DNA 修复、细胞周期控制、有丝分裂进展和治疗抵抗。研究结果与临床数据集和生物信息学分析进行了对比。
我们的研究强调了 RNF144B 作为肿瘤抑制因子的关键作用，特别是在肺腺癌中。在人类和鼠源性表达癌基因的细胞中，RNF144B 的缺乏加剧了细胞的增殖和转化。蛋白质组学和转录组学分析揭示了 RNF144B 在调节与细胞周期进展、DNA 损伤反应和基因组稳定性相关的蛋白降解方面的新功能。RNF144B 的缺乏导致染色体不稳定、有丝分裂缺陷，并与人类肿瘤中的高倍体和预后不良相关。此外，RNF144B 缺陷的肺腺癌细胞对诱导染色体不稳定的细胞周期抑制剂具有抗性。
临床数据支持我们的研究表明，RNF144B 在肿瘤抑制过程中维持基因组稳定性方面发挥着关键作用。
