Methylation of HBP1 by PRMT1 inhibits its tumor-suppressive function through regulating 2 GSN-mediated actin cytoskeleton remodeling

HBP1 is a sequence-specific transcription factor which acts as a tumor inhibitor. HBP1 exerts tumor-suppressive function through regulating the expression of many genes during cell metabolism and cell cycle process. Posttranslational modification of HBP1 is crucial for its function. In this study, we found that HBP1 was methylated at R378 by PRMT1, which decreased 16 HBP1 protein stability by promoting its ubiquitination and proteasome-mediated degradation. PRMT1-mediated methylation of HBP1 could alleviate the repressive effects of HBP1 on tumor metastasis and growth through regulation of GSN expression. GSN was identified as a novel target gene of HBP1. Methylation of HBP1 promoted actin cytoskeleton remodeling and tumor progression by downregulating GSN levels. The methylated HBP1-GSN axis was also associated with the clinical outcomes of cancer patients. Targeting methylated HBP1-GSN axis may provide a therapeutic strategy for cancer. Significance: This investigation elucidated the mechanism of how methylation of HBP1 at R378 inhibits its tumor-suppressive function and promotes actin cytoskeleton remodeling, thus providing the strategy for targeting HBP1 during cancer treatment. Overall design: Comparative gene expression profiling analysis of RNA-seq data for Hela cells(WT HBP1) and its mut derivatives (HBP1 R378A).

HBP1是一种序列特异性转录因子，可作为肿瘤抑制因子。HBP1通过调控细胞代谢与细胞周期进程中诸多基因的表达，发挥抑瘤功能。HBP1的翻译后修饰对其功能至关重要。本研究发现，蛋白质精氨酸甲基转移酶1（PRMT1）可使HBP1在R378位点发生甲基化，通过促进其泛素化与蛋白酶体介导的降解，降低HBP1蛋白稳定性。PRMT1介导的HBP1甲基化可通过调控凝溶胶蛋白（GSN）的表达，减弱HBP1对肿瘤转移与生长的抑制作用。GSN被鉴定为HBP1的新型靶基因。HBP1的甲基化通过下调GSN的表达水平，促进肌动蛋白细胞骨架重塑与肿瘤进展。甲基化HBP1-GSN信号轴还与癌症患者的临床预后相关。靶向甲基化HBP1-GSN信号轴或可为癌症治疗提供新的治疗策略。

研究意义：本研究阐明了HBP1在R378位点的甲基化如何抑制其抑瘤功能并促进肌动蛋白细胞骨架重塑的分子机制，从而为癌症治疗中靶向HBP1提供了策略依据。

整体实验设计：对表达野生型HBP1的海拉（HeLa）细胞及其突变体HBP1 R378A的RNA测序（RNA-seq）数据进行比较基因表达谱分析。