A novel isoform of Homeodomain-interacting protein kinase-2 promotes YAP/TEAD transcriptional activity in NSCLC cells
| Autor: | Jian-Hua Mao, Yinghao Wang, Yi-Lin Yang, Hiroyuki Kyoyama, Kazutsugu Uematsu, Shu Liu, Zhidong Xu, Yuyuan Dai, Liang You, David M. Jablons, Yucheng Wang |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Gene isoform Small interfering RNA HIPK2 isoform 4 5 6 7-tetrabromo-2-(1H-imidazol-2-yl)isoindoline-1 3-dione (TBID) Oncology and Carcinogenesis non-small cell lung cancer (NSCLC) Context (language use) Homeodomain Interacting Protein Kinase 2 03 medical and health sciences 0302 clinical medicine 3-dione Genetics medicine Protein kinase A Lung non-small cell lung cancer Cancer 7-tetrabromo-2-(1H-imidazol-2-yl)isoindoline-1 Gene knockdown Homeodomain Interacting Protein Kinase 2 (HIPK2) Chemistry Kinase yes-associated protein (YAP) medicine.disease respiratory tract diseases CTGF 030104 developmental biology Oncology yes-associated protein 030220 oncology & carcinogenesis Cancer research Research Paper |
| Zdroj: | Oncotarget, vol 12, iss 3 Oncotarget |
| Popis: | Homeodomain-interacting protein kinase-2 (HIPK2) can either promote or inhibit transcription depending on cellular context. In this study, we show that a new HIPK2 isoform increases TEAD reporter activity in NSCLC cells. We detected HIPK2 copy number gain in 5/6 (83.3%) NSCLC cell lines. In NSCLC patients with high HIPK2 mRNA expression in the Human Protein Atlas, the five-year survival rate is significantly lower than in patients with low expression (38% vs 47%; p = 0.047). We also found that 70/78 (89.7%) of NSCLC tissues have moderate to strong expression of the N-terminal HIPK2 protein. We detected and cloned a novel HIPK2 isoform 3 and found that its forced overexpression promotes TEAD reporter activity in NSCLC cells. Expressing HIPK2 isoform 3_K228A kinase-dead plasmid failed to increase TEAD reporter activity in NSCLC cells. Next, we showed that two siRNAs targeting HIPK2 decreased HIPK2 isoform 3 and YAP protein levels in NSCLC cells. Degradation of the YAP protein was accelerated after HIPK2 knockdown in NSCLC cells. Inhibition of HIPK2 isoform 3 decreased the mRNA expression of YAP downstream gene CTGF. The specific HIPK2 kinase inhibitor TBID decreased TEAD reporter activity, reduced cancer side populations, and inhibited tumorsphere formation of NSCLC cells. In summary, this study indicates that HIPK2 isoform 3, the main HIPK2 isoform expressed in NSCLC, promotes YAP/TEAD transcriptional activity in NSCLC cells. Our results suggest that HIPK2 isoform 3 may be a potential therapeutic target for NSCLC. |
| Databáze: | OpenAIRE |
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