Copy number amplification of TTPAL promotes cholesterol biosynthesis and esophageal squamous cell carcinoma progression via elevating NSUN2-mediated m5C modification of SREBP2 mRNA
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.
Authors
- Chunyuan Guo (ORCID: https://orcid.org/0000-0001-6769-1713)
- Rui Jiang (ORCID: https://orcid.org/0000-0003-1849-3643)
- Xinrui Ma (ORCID: https://orcid.org/0000-0002-7970-3387)
- Manyu Zhao (ORCID: https://orcid.org/0009-0006-2566-9300)
- Xianping Zhang (ORCID: https://orcid.org/0000-0002-2312-0975)
- Shan Huang (ORCID: https://orcid.org/0000-0001-8125-953X)
- Lixiao Chen (ORCID: https://orcid.org/0000-0002-7885-4351)
- Wentao Huang (ORCID: https://orcid.org/0000-0002-5469-4015)
- Zimei Peng
- Ting Wang (ORCID: https://orcid.org/0000-0003-2908-3914)
- Zhi Zheng (ORCID: https://orcid.org/0000-0002-1787-7875)
- Yuan-Yuan Liu (ORCID: https://orcid.org/0009-0000-3132-5586)
- Xing Wang (ORCID: https://orcid.org/0000-0002-8074-563X)
- Jun Rao (ORCID: https://orcid.org/0000-0003-3344-2932)
- Nimei Shen (ORCID: https://orcid.org/0000-0002-2118-4692)
- Tao Wang (ORCID: https://orcid.org/0009-0009-8230-5249)
- Lihua Mao
Institutions
- Nanjing University of Chinese Medicine (CN)
- Shanghai Jiao Tong University (CN)
- Nantong University (CN)
- Affiliated Hospital of Nantong University (CN)
- First Affiliated Hospital of Jiangxi Medical College (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Jiangxi Provincial People's Hospital (CN)
- Traditional Chinese Medicine Hospital of Kunshan (CN)
- Shanghai First People's Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Journal of Experimental & Clinical Cancer Research
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1186/s13046-025-03483-8
- Citations
- 2
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangxi Province