DYRK1B overexpression promotes senescence-like transcriptional and secretory programs in A549 lung cancer cells.

Abstract

The dual-specificity tyrosine-regulated kinase DYRK1B is frequently expressed at elevated levels in solid tumors and has been implicated in cancer cell survival, therapy resistance, and cell cycle arrest. While DYRK1B is best known for maintaining quiescence, its broader impact on cancer cell phenotypic plasticity remains incompletely understood. Using a doxycycline-inducible A549 lung adenocarcinoma model, we show that sustained overexpression of catalytically active DYRK1B induces senescence-related phenotypic changes. DYRK1B overexpression led to increased senescence-associated β-galactosidase activity, cell enlargement and granularity, and robust induction of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. RNA-sequencing revealed extensive transcriptional reprogramming, with strong overlap to established cellular senescence signatures. Gene set enrichment analysis further identified suppression of E2F target genes, consistent with durable proliferation arrest. Senescence-associated secretory phenotype (SASP) components, including PAI-1 (SERPINE1), CCL2, IGFBP7, were significantly upregulated at both mRNA and protein levels. These effects were not observed with a kinase-impaired DYRK1B mutant. Gene set enrichment analysis further identified enrichment of epithelial-mesenchymal transition (EMT) transcriptional programs, consistent with EMT-associated phenotypic effects of DYRK1B overexpression that we have reported previously. These findings identify DYRK1B as an inducer of senescence-like transcriptional and secretory programs when expressed at elevated levels in A549 lung cancer cells in vitro. Although currently speculative and awaiting in vivo validation, we hypothesize that DYRK1B-induced senescence might contribute to tumor cell persistence and therapy resistance, highlighting DYRK1B as a potential target for modulating cancer cell plasticity and senescence-associated phenotypes.