备刊底本中，替代多腺苷酸化（APA）是一种通过决定3' UTR长度的基因表达后转录调控机制，在癌症发生中起着日益重要的作用。尽管在肾透明细胞癌（KIRC）这一主要恶性肿瘤中发现了大量的APA重编程，但APA在KIRC中是否具有功能仍然未知。在本研究中，我们发现在具有APA重编程的基因中，染色质修饰因子MORC2在KIRC中获得了致癌潜能，并且此致癌潜能被3' UTR缩短通过稳定化MORC2 mRNA进一步增强。我们发现MORC2通过DNA甲基化下调肿瘤抑制因子DAPK1在KIRC中发挥功能。机制上，MORC2招募DNMT3A以促进DAPK1启动子的高甲基化，而这一过程又被MORC2的3' UTR缩短加强。此外，我们发现APA调节因子NUDT21的丧失是由DNMT3B介导的启动子甲基化引起的，这被证实是MORC2的3' UTR缩短在KIRC中的原因。此外，我们验证了NUDT21主要通过下调MORC2来发挥肿瘤抑制作用。最后，我们设计了一种反义寡核苷酸（ASO）来增强NUDT21的表达，并在体内和体外验证了其抗肿瘤作用。本研究揭示了DNMT3B/NUDT21/APA/MORC2/DAPK1调控轴在KIRC中的作用，揭示了APA在KIRC中的作用以及DNA甲基化与APA之间的相互作用。

Alternative polyadenylation (APA), a posttranscriptional mechanism of gene expression via determination of 3'UTR length, has an emerging role in carcinogenesis. Although abundant APA reprogramming is found in kidney renal clear cell carcinoma (KIRC), which is one of the major malignancies, whether APA functions in KIRC remains unknown. Herein, we found that chromatin modifier MORC2 gained oncogenic potential in KIRC among the genes with APA reprogramming, and moreover, its oncogenic potential was enhanced by 3'UTR shortening through stabilization of MORC2 mRNA. MORC2 was found to function in KIRC by downregulating tumor suppressor DAPK1 via DNA methylation. Mechanistically, MORC2 recruited DNMT3A to facilitate hypermethylation of the DAPK1 promoter, which was strengthened by 3'UTR shortening of MORC2. Furthermore, loss of APA regulator NUDT21, which was induced by DNMT3B-mediated promoter methylation, was identified as responsible for 3'UTR shortening of MORC2 in KIRC. Additionally, NUDT21 was confirmed to act as a tumor suppressor mainly depending on downregulation of MORC2. Finally, we designed an antisense oligonucleotide (ASO) to enhance NUDT21 expression and validated its antitumor effect in vivo and in vitro. This study uncovers the DNMT3B/NUDT21/APA/MORC2/DAPK1 regulatory axis in KIRC, disclosing the role of APA in KIRC and the crosstalk between DNA methylation and APA.