NSUN2通过稳定PHGDH mRNA促进丝氨酸代谢重编程来促进结直肠癌的进展。

IF 5.3 3区 医学 Q1 CELL BIOLOGY
Hao Li, Tingyue Gong, Yongheng Zhao, Yang Luo, Shuibin Tang, Tingfeng Wang, Haiping Lin, Ming Zhong
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引用次数: 0

摘要

目的:肿瘤细胞依赖丝氨酸生物合成来生长,但其在结直肠癌(CRC)中的调控尚不清楚。本研究发现m5C甲基转移酶NSUN2 (NOP2/Sun结构域家族,成员2)是丝氨酸生物合成的关键调节因子,揭示了驱动结直肠癌进展的新机制。方法:采用生物信息学分析和免疫组化(IHC)方法评价NSUN2的表达及预后价值。在体外和体内分析了NSUN2对细胞丝氨酸生物合成、细胞内活性氧(ROS)水平和凋亡水平的影响。此外,利用RNA测序、甲基化RNA免疫沉淀测序(MeRIP-seq)、RNA免疫沉淀(RIP)和RNA稳定性测定来筛选和验证NSUN2与磷酸甘油酸脱氢酶(PHGDH)之间的关联。结果:发现NSUN2在结直肠癌中高表达,并与患者生存差相关。PHGDH是NSUN2的直接下游靶点,在NSUN2介导的丝氨酸生物合成中起着至关重要的作用。此外,抑制NSUN2显著降低细胞内NADH/NAD+和NADPH/NADP+比值,导致ROS水平和凋亡水平升高,从而抑制结直肠癌的进展。此外,NSUN2通过结合“阅读器”蛋白m5C-Aly/REF输出因子(ALYREF)增强PHGDH表达和mRNA稳定性。结论:本研究确定了一个新的NSUN2/ALYREF/m5C-PHGDH轴可能是CRC的有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NSUN2 promotes colorectal cancer progression by stabilizing PHGDH mRNA to promote serine metabolism reprogramming.

Purpose: Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the m5C methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression.

Methods: The expression and prognostic value of NSUN2 were evaluated using bioinformatics analyses and immunohistochemistry (IHC) assays. The effects of NSUN2 on cellular serine biosynthesis, intracellular reactive oxygen species (ROS) levels, and apoptosis levels were analyzed both in vitro and in vivo. Additionally, RNA sequencing, Methylated RNA Immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP), and RNA stability assays were utilized to screen and validate the association between NSUN2 and phosphoglycerate dehydrogenase (PHGDH).

Results: NSUN2 was found to be highly expressed in CRC and associated with poor patient survival. PHGDH, a direct downstream target of NSUN2, plays a crucial role in NSUN2-mediated serine biosynthesis. Furthermore, inhibition of NSUN2 significantly reduced the intracellular NADH/NAD+ and NADPH/NADP+ ratios, leading to an increase in ROS levels and apoptosis levels, thereby inhibiting CRC progression. Additionally, NSUN2 enhances PHGDH expression and mRNA stability by binding to the "reader" protein m5C-Aly/REF export factor (ALYREF).

Conclusions: This study identified a novel NSUN2/ALYREF/m5C-PHGDH axis might be promising therapeutic targets for CRC.

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来源期刊
自引率
1.70%
发文量
17
审稿时长
14 weeks
期刊介绍: Cancer & Metabolism welcomes studies on all aspects of the relationship between cancer and metabolism, including: -Molecular biology and genetics of cancer metabolism -Whole-body metabolism, including diabetes and obesity, in relation to cancer -Metabolomics in relation to cancer; -Metabolism-based imaging -Preclinical and clinical studies of metabolism-related cancer therapies.
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