Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism in cancer development and progression. Poly(A) binding protein nuclear 1 (PABPN1) is a gene that encodes abundant nuclear protein, binds with high affinity to nascent poly(A) tails, and is crucial for 3'-UTR (3'-untranslated region) APA. Although PABPN1 has been recently reported as a dominant master APA regulator in clear cell renal cell carcinoma (ccRCC), the underlying functional mechanism remain unclear and the genes subject to PABPN1 regulation that contribute to ccRCC progression have not been identified. Here, we found that PABPN1 is upregulated in ccRCC, and its expression is highly associated with the clinical prognosis of ccRCC patients. PABPN1 promotes ccRCC cell proliferation, migration, invasion, and exerts an influence on sphingolipid metabolism and cell cycle. Moreover, PABPN1 depletion significantly suppressed cancer cell growth via induction of cell cycle arrest and apoptosis. In particular, we characterized PABPN1-regulated 3'-UTR APA of sphingosine-1-phosphate lyase 1 (SGPL1) and cellular repressor of E1A stimulated genes 1 (CREG1), which contribute to ccRCC progression. Collectively, our data revealed that PABPN1 promotes ccRCC progression at least in part, by suppressing SGPL1 and CREG1. Thus, PABPN1 may be a potential therapeutic target in ccRCC.

中文翻译：

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PABPN1 通过抑制 SGPL1 和 CREG1 的选择性多聚腺苷酸化促进透明细胞肾细胞癌的进展。

替代多腺苷酸化（APA）是癌症发生和进展中重要的转录后调节机制。Poly(A) 结合蛋白核 1 (PABPN1) 是编码丰富核蛋白的基因，以高亲和力与新生 Poly(A) 尾结合，并且对于 3'-UTR（3'-非翻译区）APA 至关重要。尽管 PABPN1 最近被报道为透明细胞肾细胞癌 (ccRCC) 中的主要 APA 调节因子，但其潜在的功能机制仍不清楚，并且尚未确定受 PABPN1 调节而导致 ccRCC 进展的基因。在这里，我们发现 PABPN1 在 ccRCC 中表达上调，其表达与 ccRCC 患者的临床预后高度相关。PABPN1促进ccRCC细胞增殖、迁移、侵袭，并对鞘脂代谢和细胞周期产生影响。此外，PABPN1 缺失通过诱导细胞周期停滞和细胞凋亡显着抑制癌细胞生长。特别是，我们表征了 PABPN1 调节的 1-磷酸鞘氨醇裂解酶 1 (SGPL1) 的 3'-UTR APA 和 E1A 刺激基因 1 (CREG1) 的细胞阻遏物，它们有助于 ccRCC 的进展。总的来说，我们的数据显示 PABPN1 通过抑制 SGPL1 和 CREG1 至少部分促进 ccRCC 进展。因此，PABPN1可能是ccRCC的潜在治疗靶点。