备选剪接（AS）已被认为参与细胞周期调控和癌症发生，但其潜在机制仍不清楚。多聚(U)结合剪接因子60（PUF60）对胚胎发育至关重要，并在多种癌症类型中过度表达。本文报道了PUF60通过控制细胞分裂周期25C（CDC25C）的AS促进有丝分裂细胞周期和肺癌进展。系统分析在肺腺癌（LUAD）中失调的剪接因子发现，PUF60的拷贝数和表达水平升高与预后差相关。PUF60的缺失抑制了LUAD细胞的G2/M转化、细胞增殖和肿瘤发展。在机制上，PUF60敲除导致了有丝分裂细胞周期基因（包括CDC25C）中丰富的外显子跳跃。完整的CDC25C中外显子3的跳跃会引起新生介导的mRNA衰减，并降低CDC25C蛋白的表达，从而抑制细胞增殖。本研究确立了PUF60作为肺癌的细胞周期调节因子和致癌剪接因子。版权 © 2023 The Author(s). Elsevier Inc.保留所有权利。

Alternative splicing (AS) has been implicated in cell cycle regulation and cancer, but the underlying mechanisms are poorly understood. The poly(U)-binding splicing factor 60 (PUF60) is essential for embryonic development and is overexpressed in multiple types of cancer. Here, we report that PUF60 promotes mitotic cell cycle and lung cancer progression by controlling AS of the cell division cycle 25C (CDC25C). Systematic analysis of splicing factors deregulated in lung adenocarcinoma (LUAD) identifies that elevated copy number and expression of PUF60 correlate with poor prognosis. PUF60 depletion inhibits LUAD cell-cycle G2/M transition, cell proliferation, and tumor development. Mechanistically, PUF60 knockdown leads to exon skipping enriched in mitotic cell cycle genes, including CDC25C. Exon 3 skipping in the full-length CDC25C results in nonsense-mediated mRNA decay and a decrease of CDC25C protein, thereby inhibiting cell proliferation. This study establishes PUF60 as a cell cycle regulator and an oncogenic splicing factor in lung cancer.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.