AUTHOR=Du Ying , Ye Hui , Lin Mei , Cao Lili 

TITLE=KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1267950

DOI=10.3389/fimmu.2023.1267950

ISSN=1664-3224

ABSTRACT=<sec><title>Objective</title><p>To explore the role of Krüppel-like factor 14 (KLF14) and its underlying mechanism(s) of action in cell-cycle regulation in cervical cancer.</p></sec><sec><title>Methods</title><p>Lentiviral infection was used to construct <italic>KLF14</italic>, <italic>KLF14</italic> zinc-finger structural mutations, and empty vector controls in SiHa and HeLa cervical cancer cells. The effect of KLF14 on cervical cancer cell cycle was detected by flow cytometry. The effect of KLF14 on the expression of cyclin-dependent kinase 2 (<italic>CDK2</italic>), cyclin A2 (CCNA2<italic>)</italic>, and MAPK signalling pathway-related molecules was detected by fluorescence quantitative RT-PCR (qRT-PCR) and western blot. Cervical cancer cells were treated with JNK-pathway inhibitors/agonists before we assessed changes in the cell cycle and the expression of the CDK2, CCNA2, and p-JNK/JNK. Subcutaneous xenograft studies to explore the effects of KLF14 on cervical cancer cell proliferation <italic>in vivo</italic>, and western blotting was implemented to measure the expression of CCNA2, CDK2, and the activation levels of the MAPK-signaling pathway proteins in tumours.</p></sec><sec><title>Results</title><p>The proportion of cells in the S phase was increased in the <italic>KLF14</italic>-overexpressing group compared with the control group (<italic>P</italic>&lt;0.001); CDK2, CCNA2, and <italic>p</italic>-JNK/JNK expression levels were elevated in the <italic>KLF14-</italic>overexpressing group relative to the control group (all <italic>P</italic>&lt;0.05). When JNK-pathway activation was inhibited/promoted, the proportion of cells in the S phase was reduced/increased (<italic>P</italic>&lt;0.05) and CDK2 and CCNA2 expression levels were reduced/decreased, respectively (all <italic>P</italic>&lt;0.05). Vivo experiments revealed that KLF14 inhibited cervical cancer cell proliferation (<italic>P</italic>&lt;0.01) and that <italic>p</italic>-JNK/JNK, CDK2, and CCNA2 expression levels were augmented in tumours in the overexpression group (<italic>P</italic>&lt;0.01).</p></sec><sec><title>Conclusion</title><p>KLF14 induced S-phase arrest in cervical cancer cells and inhibited the proliferation of cervical cancer cells <italic>in vivo</italic>; the induction of S-phase arrest was related to its zinc-finger structure. KLF14 also activated the JNK pathway to induce S-phase arrest and promote the expression of CDK2 and CCNA2. In summary, KLF14 activates the JNK-signaling pathway to induce S-phase arrest in cervical cancer cells</p></sec>