STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer
Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a serious clinical challenge, demanding further exploration of its pathogenesis and therapeutic targets for metastasis, the main cause of mortality. Here, we identify STN1, a CST complex member crucial for maintaining telomere lengths and genome...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-63083-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849226117176623104 |
|---|---|
| author | Di Dong Zhe Zhou Minglu Zhu Zhiyuan Hou Mo Chen Jingjing Gong Xuyang Zhao Aohui Yan Hui Liang Yuxin Yin |
| author_facet | Di Dong Zhe Zhou Minglu Zhu Zhiyuan Hou Mo Chen Jingjing Gong Xuyang Zhao Aohui Yan Hui Liang Yuxin Yin |
| author_sort | Di Dong |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a serious clinical challenge, demanding further exploration of its pathogenesis and therapeutic targets for metastasis, the main cause of mortality. Here, we identify STN1, a CST complex member crucial for maintaining telomere lengths and genome stability, as a key factor in promoting PDAC metastasis. Elevated STN1 levels correlate with poor patient survival, with oncogenic protein HOXB7 as an upstream transcription factor regulating STN1. Utilizing multiple PDAC experimental models, we discover STN1’s role in promoting metastasis by functioning as an upstream factor in epithelial-mesenchymal transition (EMT). Our mechanistic evidence suggests that during transcription, STN1 binds to structurally displaced single-stranded DNA flanking the R-loop, recruiting STAT3 to activate ZEB1 transcription independent of its known telomere maintenance function. Notably, STAT3 inhibitors show enhanced efficiency in restraining metastatic potential in STN1-overexpressed PDAC cells, offering a potential therapeutic avenue for targeting metastasis in STN1-overexpressed PDAC patients facing an unfavorable prognosis. |
| format | Article |
| id | doaj-art-1a00c02864454b3e807e5aeaef0e4284 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1a00c02864454b3e807e5aeaef0e42842025-08-24T11:36:44ZengNature PortfolioNature Communications2041-17232025-08-0116111610.1038/s41467-025-63083-0STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancerDi Dong0Zhe Zhou1Minglu Zhu2Zhiyuan Hou3Mo Chen4Jingjing Gong5Xuyang Zhao6Aohui Yan7Hui Liang8Yuxin Yin9Department of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterDepartment of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science CenterDepartment of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science CenterAbstract Pancreatic ductal adenocarcinoma (PDAC) poses a serious clinical challenge, demanding further exploration of its pathogenesis and therapeutic targets for metastasis, the main cause of mortality. Here, we identify STN1, a CST complex member crucial for maintaining telomere lengths and genome stability, as a key factor in promoting PDAC metastasis. Elevated STN1 levels correlate with poor patient survival, with oncogenic protein HOXB7 as an upstream transcription factor regulating STN1. Utilizing multiple PDAC experimental models, we discover STN1’s role in promoting metastasis by functioning as an upstream factor in epithelial-mesenchymal transition (EMT). Our mechanistic evidence suggests that during transcription, STN1 binds to structurally displaced single-stranded DNA flanking the R-loop, recruiting STAT3 to activate ZEB1 transcription independent of its known telomere maintenance function. Notably, STAT3 inhibitors show enhanced efficiency in restraining metastatic potential in STN1-overexpressed PDAC cells, offering a potential therapeutic avenue for targeting metastasis in STN1-overexpressed PDAC patients facing an unfavorable prognosis.https://doi.org/10.1038/s41467-025-63083-0 |
| spellingShingle | Di Dong Zhe Zhou Minglu Zhu Zhiyuan Hou Mo Chen Jingjing Gong Xuyang Zhao Aohui Yan Hui Liang Yuxin Yin STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer Nature Communications |
| title | STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer |
| title_full | STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer |
| title_fullStr | STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer |
| title_full_unstemmed | STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer |
| title_short | STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer |
| title_sort | stn1 facilitates metastasis by promoting transcription of emt activator zeb1 in pancreatic cancer |
| url | https://doi.org/10.1038/s41467-025-63083-0 |
| work_keys_str_mv | AT didong stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT zhezhou stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT mingluzhu stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT zhiyuanhou stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT mochen stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT jingjinggong stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT xuyangzhao stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT aohuiyan stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT huiliang stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer AT yuxinyin stn1facilitatesmetastasisbypromotingtranscriptionofemtactivatorzeb1inpancreaticcancer |