A novel isoform of Homeodomain-interacting protein kinase-2 promotes YAP/TEAD transcriptional activity in NSCLC cells
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Yuyuan Dai1,2,*, Hiroyuki Kyoyama1,3,*, Yi-Lin Yang1,*, Yucheng Wang1, Shu Liu1, Yinghao Wang1, Jian-Hua Mao4, Zhidong Xu1, Kazutsugu Uematsu3, David M. Jablons1 and Liang You1
1 Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, USA
2 Model Animal Research Center of Nanjing University, Nanjing, Jiangsu, China
3 Department of Pulmonary Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
4 Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
* These authors contributed equally to this work
|Liang You,||email:||[email protected]|
Keywords: Homeodomain Interacting Protein Kinase 2 (HIPK2); non-small cell lung cancer (NSCLC); yes-associated protein (YAP); HIPK2 isoform; 4,5,6,7-tetrabromo-2-(1H-imidazol-2-yl)isoindoline-1,3-dione (TBID)
Received: August 22, 2019 Accepted: April 03, 2020 Published: February 02, 2021
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.
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