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Background <p>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.</p> Methods <p>We examined the expression and functional impact of a DAPK1 splice variant, <i>DAPK1-215</i>, in multiple cancer cell lines. DAPK1 and <i>DAPK1-215</i> 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 <i>DAPK1-215</i> and <i>DAPK1</i> mRNA levels.</p> Results <p><i>DAPK1-215</i> downregulated DAPK1 expression in liver, kidney, and gastric cancer cells by reducing <i>DAPK1</i> mRNA stability. <i>DAPK1-215</i> 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 <i>DAPK1-215</i> and <i>DAPK1</i> mRNAs, suggesting that <i>DAPK1-215</i> may act by competing for DDX3X binding to modulate <i>DAPK1</i> mRNA stability. Importantly, high levels of <i>DAPK1-215</i> correlated inversely with <i>DAPK1</i> mRNA in liver cancer specimens and predicted poor prognosis, whereas high DAPK1 expression predicted improved patient outcomes.</p> Conclusions <p>Our findings unveil <i>DAPK1-215</i> as a molecular brake on DAPK1 expression, influencing cancer cell migration and invasion in a context-dependent manner. These results highlight the potential of <i>DAPK1-215</i> as an important regulator of malignant progression and as a prognostic marker in liver cancer.</p>

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Modulation of DAPK1 expression by its alternative splice variant DAPK1-215 in cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月20日

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  • QingShui Wang,
  • ShuYun Weng,
  • WenTing Zhong,
  • YouYu Lin,
  • Yan Yu,
  • YiMin Huang,
  • LiLin Ge,
  • XiuLi Zhang,
  • FangQin Xue,
  • Yehuda G. Assaraf,
  • Yao Lin

摘要

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.