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<p>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 (<i>TTPAL</i>) is highly amplified and frequently overexpressed in human ESCC. Using <i>Ttpal-</i>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 <i>SREBP2</i> mRNA, and then the m5C modified <i>SREBP2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月26日

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  • 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

摘要

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.