The precise maintenance of PTEN dosage is crucial for tumor suppression across a wide variety of cancers. Post-transcriptional regulation of Pten heavily relies on regulatory elements encoded by its 3’UTR. We previously reported the important diversity of 3’UTR isoforms of Pten mRNAs produced through alternative polyadenylation (APA). Here, we reveal the direct regulation of Pten APA by the mammalian cleavage factor I (CFIm) complex, which in turn contributes to PTEN protein dosage. CFIm consists of the UGUA-binding CFIm25 and APA regulatory subunits CFIm59 or CFIm68. Deep sequencing analyses of perturbed (KO and KD) cell lines uncovered the differential regulation of Pten APA by CFIm59 and CFIm68 and further revealed that their divergent functions have widespread impact for APA in transcriptomes. Differentially regulated genes include numerous factors within the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling pathway that PTEN counter-regulates. We further reveal a stratification of APA dysregulation among a subset of PTEN-driven cancers, with recurrent alterations among PI3K/Akt pathway genes regulated by CFIm. Our results refine the transcriptome selectivity of the CFIm complex in APA regulation, and the breadth of its impact in PTEN-driven cancers.

中文翻译：

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CFIm59 和 CFIm68 在 Pten 的 mRNA 替代多聚腺苷酸化和 PI3K/Akt 信号级联中的不同、相反的功能

PTEN 剂量的精确维持对于多种癌症的肿瘤抑制至关重要。Pten的转录后调控严重依赖于由其 3'UTR 编码的调控元件。我们之前报道了通过替代聚腺苷酸化 (APA) 产生的Pten mRNA的 3'UTR 异构体的重要多样性。在这里，我们揭示了哺乳动物裂解因子 I (CFIm) 复合物对Pten APA的直接调节，这反过来又有助于 PTEN 蛋白剂量。CFIm 由结合 UGUA 的 CFIm25 和 APA 调节亚基 CFIm59 或 CFIm68 组成。对扰动（KO 和 KD）细胞系的深度测序分析揭示了Pten的差异调节CFIm59 和 CFIm68 的 APA 进一步揭示了它们不同的功能对转录组中的 APA 具有广泛的影响。差异调节的基因包括磷酸肌醇 3-激酶 (PI3K)/蛋白激酶 B (Akt) 信号通路中的许多因子，PTEN 反调节。我们进一步揭示了PTEN 驱动的癌症亚群中 APA 失调的分层，以及由 CFIm 调节的 PI3K/Akt 通路基因之间的反复改变。我们的结果改进了 CFIm 复合物在 APA 调节中的转录组选择性，以及其对PTEN驱动的癌症的影响范围。