PDF(Pubmed)
Abstract：
Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and post-transcriptional regulation. Moreover, PTBP1 has been implicated as a causal factor in tumorigenesis. However, the involvement of PTBP1 in cellular senescence, a key biological process in aging and cancer suppression, remains to be clarified. Here, it is shown that PTBP1 is associated with the facilitation of tumor growth and the prognosis in lung adenocarcinoma (LUAD). PTBP1 exhibited significantly increased expression in various cancer types including LUAD and showed consistently decreased expression in multiple cellular senescence models. Suppression of PTBP1 induced cellular senescence in LUAD cells. In terms of molecular mechanisms, the silencing of PTBP1 enhanced the skipping of exon 3 in F-box protein 5 (FBXO5), resulting in the generation of a less stable RNA splice variant, FBXO5-S, which subsequently reduces the overall FBXO5 expression. Additionally, downregulation of FBXO5 was found to induce senescence in LUAD. Collectively, these findings illustrate that PTBP1 possesses an oncogenic function in LUAD through inhibiting senescence, and that targeting aberrant splicing mediated by PTBP1 has therapeutic potential in cancer treatment.
摘要：
聚嘧啶束结合蛋白1(PTBP1)在剪接和转录后调控中起重要作用。此外，PTBP1已被认为是肿瘤发生的原因。然而,PTBP1参与细胞衰老，衰老和癌症抑制的关键生物学过程，还有待澄清。这里,结果表明，PTBP1与肺腺癌（LUAD）的肿瘤生长和预后有关。PTBP1在包括LUAD在内的各种癌症类型中表现出显著增加的表达,并且在多种细胞衰老模型中表现出一致降低的表达。抑制PTBP1诱导LUAD细胞中的细胞衰老。从分子机制来看,PTBP1的沉默增强了F-box蛋白5（FBXO5）外显子3的跳跃，导致产生不太稳定的RNA剪接变体，FBXO5-S,这随后降低了FBXO5的整体表达。此外,发现FBXO5的下调可诱导LUAD衰老。总的来说，这些发现说明PTBP1通过抑制衰老在LUAD中具有致癌功能，靶向PTBP1介导的异常剪接在癌症治疗中具有治疗潜力。
