Transcriptional induction of NF-κB-inducing kinase by E2F4/5 facilitates collective invasion of GBM cells

The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is extremely poor due to the highly invasive nature of these aggressive cancers. Previous work has demonstrated that TNF-weak like factor (TWEAK) induction of the noncanonical NF-.B pathway promotes the invasiveness of GBM cells in an NF-kappa B-inducing kinase (NIK)-dependent manner. While NIK activity is predominantly regulated at the posttranslational level, we show here that NIK (MAP3K14) is upregulated at the transcriptional level in invading cell populations, with the highest NIK expression observed in the most invasive cells. GBM cells with high induction of NIK gene expression demonstrate characteristics of collective invasion, facilitating invasion of neighboring cells. Furthermore, we demonstrate that the E2F transcription factors E2F4 and E2F5 directly regulate NIK transcription and are required to promote GBM cell invasion in response to TWEAK. Overall, our findings demonstrate that transcriptional induction of NIK facilitates collective cell migration and invasion, thereby promoting GBM pathogenesis.

Automated summary

The prognosis of high-grade gliomas, such as glioblastoma multiforme (GBM), is very poor due to their highly invasive nature. Previous studies have shown that TWEAK can promote the invasiveness of GBM cells through the noncanonical NF-.B pathway, with NIK being a key player. Our study reveals that NIK is upregulated at the transcriptional level in invading cells, and high expression of NIK facilitates collective invasion of GBM cells. Additionally, we demonstrate that E2F4 and E2F5 transcription factors are involved in the regulation of NIK transcription and the promotion of GBM cell invasion in response to TWEAK.