The Key Laboratory of Molecular Biology of Infectious Diseases Designated By the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646000, China.
Exp Cell Res. 2021 Dec 1;409(1):112898. doi: 10.1016/j.yexcr.2021.112898. Epub 2021 Oct 29.
The nuclear matrix-associated protein Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), also known as SAF-A, is known to maintain active chromatin structure in mouse hepatocytes. However, the functional roles and molecular mechanisms of HNRNPU in the development of hepatocellular carcinoma (HCC) remain largely unknown. Herein, we found that HNRNPU was upregulated in HCC, and the proliferation of HCC cells was inhibited in vitro and in vivo upon HNRNPU knockdown. Moreover, the upregulation of HNRNPU was correlated with poor prognosis in HCC. Mechanistically, HNRNPU bound to the CDK2 gene locus, a key factor in cell cycle regulation, where it was enriched with H3K27 acetylation (H3K27ac), H3K9 acetylation (H3K9ac), and H3K4 mono-methylation (H3K4me1). Furthermore, HNRNPU knockdown reduced the levels of H3K27ac and H3K9ac at the binding site, where the levels of H3K27 tri-methylation (H3K27me3) were increased, eventually leading to the downregulation of CDK2. Collectively, our results provide a new mechanism whereby HNRNPU promotes HCC development by enhancing the transcription of CDK2.
核基质相关蛋白异质性核核糖核蛋白 U（HNRNPU），也称为 SAF-A，已知在小鼠肝细胞中维持活性染色质结构。然而，HNRNPU 在肝细胞癌（HCC）发展中的功能作用和分子机制在很大程度上仍然未知。在此，我们发现 HNRNPU 在 HCC 中上调，并且在 HCC 细胞的体外和体内敲低 HNRNPU 可抑制其增殖。此外，HNRNPU 的上调与 HCC 的预后不良相关。在机制上，HNRNPU 与细胞周期调节的关键因子 CDK2 基因座结合，在该处富含 H3K27 乙酰化（H3K27ac）、H3K9 乙酰化（H3K9ac）和 H3K4 单甲基化（H3K4me1）。此外，HNRNPU 敲低降低了结合位点处的 H3K27ac 和 H3K9ac 水平，H3K27 三甲基化（H3K27me3）水平升高，最终导致 CDK2 下调。总之，我们的结果提供了一种新的机制，即 HNRNPU 通过增强 CDK2 的转录来促进 HCC 的发展。
