Copy number amplification of TTPAL promotes cholesterol biosynthesis and esophageal squamous cell carcinoma progression via elevating NSUN2-mediated m5C modification of SREBP2 mRNA.

IF 12.8 1区 医学 Q1 ONCOLOGY
Shan Huang, Yuanyuan Liu, Manyu Zhao, Tao Wang, Lihua Mao, Ting Wang, Chunyuan Guo, Wentao Huang, Zimei Peng, Zhen Zhang, Rui Jiang, Xinrui Ma, Nimei Shen, Jun Rao, Xing Wang, Zhi Zheng, Lixiao Chen
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引用次数: 0

Abstract

Alterations in copy number are crucial genetic events in the development of esophageal squamous cell carcinoma (ESCC). Here, we show that Tocopherol alpha transfer protein-like (TTPAL) is highly amplified and frequently overexpressed in human ESCC. Using Ttpal-KO mouse mode, we demonstrate that TTPAL promotes ESCC cell proliferation and accelerates tumor development by driving cholesterol biosynthesis. Mechanistically, TTPAL upregulates a key transcription factor in cholesterol biosynthesis-sterol regulatory element-binding transcription factor (SREBP2) in ESCC cells. TTPAL interacts with the RNA methyltransferase NSUN2 and relieves the ubiquitination of NSUN2, protecting NSUN2 from proteasome-mediated degradation. In turn, NSUN2 catalyzes the m5C modification of SREBP2 mRNA, and then the m5C modified SREBP2 mRNA binds to the m5C reader protein-ALYREF to enhance its stability, thereby increasing SREBP2 expression. Moreover, we validate the efficacy of cholesterol biosynthesis inhibitor simvastatin in ESCC with high TTPAL expression. Overall, our results uncover a novel function of TTPAL in regulating SREBP2 expression, revealed a previously unknown TTPAL/NSUN2/SREBP2 pathway that promotes cholesterol biosynthesis in ESCC cells, and identified sensitively to cholesterol biosynthesis inhibitor simvastatin.

TTPAL的拷贝数扩增通过提高nsun2介导的SREBP2 mRNA的m5C修饰,促进胆固醇的生物合成和食管鳞状细胞癌的进展。
拷贝数的改变是食管鳞状细胞癌(ESCC)发展过程中至关重要的遗传事件。在这里,我们发现生育酚α转移蛋白样蛋白(TTPAL)在人ESCC中高度扩增并经常过表达。通过TTPAL - ko小鼠模型,我们证明TTPAL通过驱动胆固醇生物合成促进ESCC细胞增殖并加速肿瘤发展。在机制上,TTPAL上调ESCC细胞中胆固醇生物合成的关键转录因子-甾醇调节元件结合转录因子(SREBP2)。TTPAL与RNA甲基转移酶NSUN2相互作用,减轻NSUN2的泛素化,保护NSUN2免受蛋白酶体介导的降解。反过来,NSUN2催化m5C修饰SREBP2 mRNA, m5C修饰的SREBP2 mRNA结合m5C解读蛋白- alyref增强其稳定性,从而增加SREBP2的表达。此外,我们验证了胆固醇生物合成抑制剂辛伐他汀对高TTPAL表达的ESCC的疗效。总之,我们的研究结果揭示了TTPAL调控SREBP2表达的新功能,揭示了以前未知的TTPAL/NSUN2/SREBP2通路促进ESCC细胞中的胆固醇生物合成,并对胆固醇生物合成抑制剂辛伐他汀敏感。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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