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CPSF1抑制促进基因间聚腺苷酸化位点的广泛使用并损害前列腺癌细胞中的糖酵解。

CPSF1 inhibition promotes widespread use of intergenic polyadenylation sites and impairs glycolysis in prostate cancer cells.

作者信息

Tietz Kiel T, McCluskey Braedan M, Miller Conor R, Li Yingming, Munro Sarah A, Dehm Scott M

机构信息

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.

Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.

出版信息

Cell Rep. 2025 Jan 28;44(1):115211. doi: 10.1016/j.celrep.2024.115211. Epub 2025 Jan 22.

DOI:10.1016/j.celrep.2024.115211
PMID:39847481
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11831233/
Abstract

Localized prostate cancer can be cured by radiation or surgery, but advanced prostate cancer continues to be a clinical challenge. Altered alternative polyadenylation occurs in numerous cancers and can downregulate tumor-suppressor genes and upregulate oncogenes. We found that the cleavage and polyadenylation specificity factor (CPSF) complex factor CPSF1 is upregulated in patients with advanced prostate cancer, with high CPSF1 expression correlating with worse progression-free survival. Knockdown of CPSF1 selectively inhibited the growth of prostate cancer cells and reduced glycolytic output. Evaluating the changes in global poly(A) site usage in prostate cancer cells following CPSF1 knockdown revealed widespread usage of intergenic poly(A) sites distal to annotated 3' UTRs, which lengthened 3' UTRs and decreased levels of thousands of mRNAs, including key glycolysis genes. These findings uncover a role for CPSF1 in the suppression of intergenic poly(A) sites in prostate cancer and nominate CPSF1 as a therapeutic target in advanced prostate cancer.

摘要

局限性前列腺癌可通过放疗或手术治愈，但晚期前列腺癌仍然是一项临床挑战。可变聚腺苷酸化改变在众多癌症中都会出现，并且能够下调肿瘤抑制基因并上调癌基因。我们发现，在晚期前列腺癌患者中，切割和聚腺苷酸化特异性因子（CPSF）复合物因子CPSF1上调，CPSF1高表达与无进展生存期较差相关。敲低CPSF1可选择性抑制前列腺癌细胞的生长并降低糖酵解产量。评估CPSF1敲低后前列腺癌细胞中全局聚腺苷酸化位点使用情况的变化，发现注释的3'UTR远端的基因间聚腺苷酸化位点广泛使用，这延长了3'UTR并降低了数千种mRNA的水平，包括关键糖酵解基因。这些发现揭示了CPSF1在抑制前列腺癌基因间聚腺苷酸化位点中的作用，并将CPSF1指定为晚期前列腺癌的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/eb8ec900ac65/nihms-2052781-f0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/78e28909cbc4/nihms-2052781-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/8e76c4bdeacc/nihms-2052781-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/eb8ec900ac65/nihms-2052781-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/4f473f06a03d/nihms-2052781-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/ef510fa836a9/nihms-2052781-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/78b357954872/nihms-2052781-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/78e28909cbc4/nihms-2052781-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/8e76c4bdeacc/nihms-2052781-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44df/11831233/eb8ec900ac65/nihms-2052781-f0006.jpg

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本文引用的文献

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RNA. 2024 Feb 16;30(3):281-297. doi: 10.1261/rna.079931.123.
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Therapeutic targeting of CPSF3-dependent transcriptional termination in ovarian cancer.在卵巢癌中靶向 CPSF3 依赖性转录终止的治疗。
Sci Adv. 2023 Nov 24;9(47):eadj0123. doi: 10.1126/sciadv.adj0123. Epub 2023 Nov 22.
3
CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation.
CPSF6 通过相分离调节癌细胞的可变多聚腺苷酸化和增殖。
Cell Rep. 2023 Oct 31;42(10):113197. doi: 10.1016/j.celrep.2023.113197. Epub 2023 Sep 30.
4
Elevated pre-mRNA 3' end processing activity in cancer cells renders vulnerability to inhibition of cleavage and polyadenylation.癌细胞中升高的前体 mRNA 3' 端加工活性使其易受切割和多聚腺苷酸化抑制的影响。
Nat Commun. 2023 Aug 1;14(1):4480. doi: 10.1038/s41467-023-39793-8.
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The Genomic and Epigenomic Landscape of Double-Negative Metastatic Prostate Cancer.双阴性转移性前列腺癌的基因组和表观基因组景观。
Cancer Res. 2023 Aug 15;83(16):2763-2774. doi: 10.1158/0008-5472.CAN-23-0593.
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CPSF1 positively regulates NSDHL by alternative polyadenylation and promotes gastric cancer progression.CPSF1通过可变多聚腺苷酸化正向调控NSDHL并促进胃癌进展。
Am J Cancer Res. 2022 Oct 15;12(10):4566-4583. eCollection 2022.
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