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

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

  • J Exp Clin Cancer Res. 2025 Jul 26;44(1):220. doi: 10.1186/s13046-025-03483-8.
Shan Huang # 1,  Yuanyuan Liu # 2,  Manyu Zhao # 3,  Tao Wang # 4,  Lihua Mao 1,  Ting Wang 1,  Chunyuan Guo 1,  Wentao Huang 1,  Zimei Peng 5,  Zhen Zhang 5,  Rui Jiang 6,  Xinrui Ma 7,  Nimei Shen 8,  Jun Rao 9,  Xing Wang 10 11,  Zhi Zheng 12,  Lixiao Chen 13
Affiliations

Affiliations

  • 1 Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
  • 2 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 3 National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430074, China.
  • 4 Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, PR China.
  • 5 Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China.
  • 6 Department of Otolaryngology: Head and Neck Surgery, Nanjing University of Chinese Medicine Affiliated Kunshan Traditional Chinese Medicine Hospital, Jiangsu, 215300, China.
  • 7 Department of Otolaryngology: Head and Neck Surgery, The First People's Hospital of Kunshan, Jiangsu, 215300, China.
  • 8 Department of Otolaryngology: Head and Neck Surgery, Jiangsu General Hospital, The Second Affiliated Hospital of Nantong University, Jiangsu, 226000, China.
  • 9 The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for Cancer, Nanchang, 330006, China. raojun1986@126.com.
  • 10 Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China. qieshuidao@126.com.
  • 11 Centre for Medical Research and Translation, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China. qieshuidao@126.com.
  • 12 Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, China. zhengxia_2007@163.com.
  • 13 Department of Otolaryngology: Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. Chenlixiao1201@163.com.
  • # Contributed equally.
PMID: 40713894 DOI: 10.1186/s13046-025-03483-8
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.

Keywords

Esophageal squamous cell carcinoma; NSUN2; Reprogrammed cholesterol metabolism; SREBP2; Simvastatin therapy resistance; TTPAL.

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