In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma

Jason K. Sa, Yeup Yoon, Misuk Kim, Yeonghwan Kim, Hee Jin Cho, Jin Ku Lee, Gi Soo Kim, Suji Han, Woon Jin Kim, Yong Jae Shin, Kyeung Min Joo, Patrick J. Paddison, Tohru Ishitani, Jeongwu Lee, Do Hyun Nam

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16 Citations (Scopus)

Abstract

Glioblastoma (GBM) is the most lethal brain cancer with profound genomic alterations. While the bona fide tumor suppressor genes such as PTEN, NF1, and TP53 have high frequency of inactivating mutations, there may be the genes with GBM-suppressive roles for which genomic mutation is not a primary cause for inactivation. To identify such genes, we employed in vivo RNAi screening approach using the patient-derived GBM xenograft models. We found that Nemo-Like Kinase (NLK) negatively regulates mesenchymal activities, a characteristic of aggressive GBM, in part via inhibition of WNT/β-catenin signaling. Consistent with this, we found that NLK expression is especially low in a subset of GBMs that harbors high WNT/mesenchymal activities. Restoration of NLK inhibited WNT and mesenchymal activities, decreased clonogenic growth and survival, and impeded tumor growth in vivo. These data unravel a tumor suppressive role of NLK and support the feasibility of combining oncogenomics with in vivo RNAi screen.

Original languageEnglish
Pages (from-to)20145-20159
Number of pages15
JournalOncotarget
Volume6
Issue number24
DOIs
Publication statusPublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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    Sa, J. K., Yoon, Y., Kim, M., Kim, Y., Cho, H. J., Lee, J. K., Kim, G. S., Han, S., Kim, W. J., Shin, Y. J., Joo, K. M., Paddison, P. J., Ishitani, T., Lee, J., & Nam, D. H. (2015). In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma. Oncotarget, 6(24), 20145-20159. https://doi.org/10.18632/oncotarget.3980