Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer
Abstract Background Death-Associated Protein Kinase 1 (DAPK1) family members are calcium/calmodulin-regulated serine/threonine kinases implicated in cell death, normal development, and human diseases. However, the regulation of DAPK1 expression in cancer remains unclear. Methods We examined the expr...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06127-9 |
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| author | QingShui Wang ShuYun Weng WenTing Zhong YouYu Lin Yan Yu YiMin Huang LiLin Ge XiuLi Zhang FangQin Xue Yehuda G. Assaraf Yao Lin |
| author_facet | QingShui Wang ShuYun Weng WenTing Zhong YouYu Lin Yan Yu YiMin Huang LiLin Ge XiuLi Zhang FangQin Xue Yehuda G. Assaraf Yao Lin |
| author_sort | QingShui Wang |
| collection | DOAJ |
| description | Abstract Background Death-Associated Protein Kinase 1 (DAPK1) family members are calcium/calmodulin-regulated serine/threonine kinases implicated in cell death, normal development, and human diseases. However, the regulation of DAPK1 expression in cancer remains unclear. Methods We examined the expression and functional impact of a DAPK1 splice variant, DAPK1-215, in multiple cancer cell lines. DAPK1 and DAPK1-215 expression levels were quantified by qRT-PCR and Western blotting. Cell migration, invasion, and proliferation assays were conducted in vitro, and a zebrafish model was employed to evaluate metastatic potential. RNA pull-down and CLIP-seq analyses were performed to identify potential RNA-binding proteins. Finally, clinical liver cancer specimens were analyzed to assess the prognostic relevance of DAPK1-215 and DAPK1 mRNA levels. Results DAPK1-215 downregulated DAPK1 expression in liver, kidney, and gastric cancer cells by reducing DAPK1 mRNA stability. DAPK1-215 promoted migratory and invasive capabilities in liver and kidney cancer cells, but inhibited these processes in gastric cancer cells, without affecting cell proliferation. Mechanistically, DEAD-Box Helicase 3 X-Linked (DDX3X) stabilized both DAPK1-215 and DAPK1 mRNAs, suggesting that DAPK1-215 may act by competing for DDX3X binding to modulate DAPK1 mRNA stability. Importantly, high levels of DAPK1-215 correlated inversely with DAPK1 mRNA in liver cancer specimens and predicted poor prognosis, whereas high DAPK1 expression predicted improved patient outcomes. Conclusions Our findings unveil DAPK1-215 as a molecular brake on DAPK1 expression, influencing cancer cell migration and invasion in a context-dependent manner. These results highlight the potential of DAPK1-215 as an important regulator of malignant progression and as a prognostic marker in liver cancer. |
| format | Article |
| id | doaj-art-caa6f0509bb34491830d639e3f961648 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-caa6f0509bb34491830d639e3f9616482025-01-26T12:50:10ZengBMCJournal of Translational Medicine1479-58762025-01-0123111510.1186/s12967-025-06127-9Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancerQingShui Wang0ShuYun Weng1WenTing Zhong2YouYu Lin3Yan Yu4YiMin Huang5LiLin Ge6XiuLi Zhang7FangQin Xue8Yehuda G. Assaraf9Yao Lin10Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese MedicineXiamen Ocean Vocational CollegeThe United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, The Liver Center of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian Medical UniversityFujian Normal UniversityCollaborative Innovation Center for Rehabilitation Technology, the Institute of Rehabilitation Industry, Fujian University of Traditional Chinese MedicineCollege of Pharmacy, Fujian University of Traditional Chinese MedicineJiangsu Province Engineering Research Center of Chinese Medicine Health CareFujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese MedicineDepartment of Gastrointestinal Surgery, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical UniversityThe Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of TechnologyFujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese MedicineAbstract Background Death-Associated Protein Kinase 1 (DAPK1) family members are calcium/calmodulin-regulated serine/threonine kinases implicated in cell death, normal development, and human diseases. However, the regulation of DAPK1 expression in cancer remains unclear. Methods We examined the expression and functional impact of a DAPK1 splice variant, DAPK1-215, in multiple cancer cell lines. DAPK1 and DAPK1-215 expression levels were quantified by qRT-PCR and Western blotting. Cell migration, invasion, and proliferation assays were conducted in vitro, and a zebrafish model was employed to evaluate metastatic potential. RNA pull-down and CLIP-seq analyses were performed to identify potential RNA-binding proteins. Finally, clinical liver cancer specimens were analyzed to assess the prognostic relevance of DAPK1-215 and DAPK1 mRNA levels. Results DAPK1-215 downregulated DAPK1 expression in liver, kidney, and gastric cancer cells by reducing DAPK1 mRNA stability. DAPK1-215 promoted migratory and invasive capabilities in liver and kidney cancer cells, but inhibited these processes in gastric cancer cells, without affecting cell proliferation. Mechanistically, DEAD-Box Helicase 3 X-Linked (DDX3X) stabilized both DAPK1-215 and DAPK1 mRNAs, suggesting that DAPK1-215 may act by competing for DDX3X binding to modulate DAPK1 mRNA stability. Importantly, high levels of DAPK1-215 correlated inversely with DAPK1 mRNA in liver cancer specimens and predicted poor prognosis, whereas high DAPK1 expression predicted improved patient outcomes. Conclusions Our findings unveil DAPK1-215 as a molecular brake on DAPK1 expression, influencing cancer cell migration and invasion in a context-dependent manner. These results highlight the potential of DAPK1-215 as an important regulator of malignant progression and as a prognostic marker in liver cancer.https://doi.org/10.1186/s12967-025-06127-9DAPK1DAPK1-215DDX3XMRNA stabilityCancer progression |
| spellingShingle | QingShui Wang ShuYun Weng WenTing Zhong YouYu Lin Yan Yu YiMin Huang LiLin Ge XiuLi Zhang FangQin Xue Yehuda G. Assaraf Yao Lin Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer Journal of Translational Medicine DAPK1 DAPK1-215 DDX3X MRNA stability Cancer progression |
| title | Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer |
| title_full | Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer |
| title_fullStr | Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer |
| title_full_unstemmed | Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer |
| title_short | Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer |
| title_sort | modulation of dapk1 expression by its alternative splice variant dapk1 215 in cancer |
| topic | DAPK1 DAPK1-215 DDX3X MRNA stability Cancer progression |
| url | https://doi.org/10.1186/s12967-025-06127-9 |
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