NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1

Authors: JONNAKUTI, VENKATA - Baylor College Of Medicine; JI, PING - University Of Texas Medical Branch; GAO, YIPENG - Baylor College Of Medicine; LIN, AI - University Of Texas Medical Branch; CHU, YUAN - University Of Texas Medical Branch; ELROD, NATHAN - University Of Texas Medical Branch; HUANG, KAI-LIEH - University Of Rochester; LI, WEI - University Of California Irvine; YALAMANCHILI, HARI - Children'S Nutrition Research Center (CNRC); WAGNER, ERIC - University Of Rochester

Submitted to: Journal of Neuro-Oncology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2023
Publication Date: 6/30/2023
Citation: Jonnakuti, V.S., Ji, P., Gao, Y., Lin, A., Chu, Y., Elrod, N., Huang, K., Li, W., Yalamanchili, H.K., Wagner, E.J. 2023. NUDT21 alters glioma migration through differential alternative polyadenylation of LAMC1. Journal of Neuro-Oncology. https://doi.org/10.1007/s11060-023-04370-y.
DOI: https://doi.org/10.1007/s11060-023-04370-y

Interpretive Summary: When it comes to brain cancer, gliomas a type of brain tumor that arises from glial cells that account for 27% of all brain and central nervous system tumors in the United States. Gliomas can have a significant health burden on affected individuals, their families, and society. Additionally, the economic burden associated with glioma is substantial, considering the costs of diagnosis, treatment, rehabilitation, supportive care, and potential long-term effects. Therefore, reducing the health burden of glioma through research and advancements in treatment is essential for improving patient outcomes and minimizing the socioeconomic impact. Our team used an advanced scientific method, similar to a complex code-breaking system, to decode and analyze how a molecule called NUDT21 changes the way messages are processed in brain cancer cells. What we found was fascinating. We discovered that a molecule called LAMC1, is significantly affected by NUDT21. Think of NUDT21 as a molecular switch that controls how the message from LAMC1 is read. When we turned off this switch (or 'knocked it down' in scientific terms), it led to the creation of a shorter message from LAMC1. This, in turn, led to more LAMC1 being produced resulting in more active brain cancer cells. Understanding these interactions could provide a new avenue for brain cancer treatment. By controlling this process, we could potentially slow down or stop the spread of brain cancer, offering hope for better patient outcomes.

Technical Abstract: Glioma is a type of brain tumor that arises from glial cells, which are supportive cells in the brain. Gliomas and their surrounding microenvironment constantly interact to promote tumorigenicity, yet the underlying posttranscriptional regulatory mechanisms that govern this interplay are poorly understood. Utilizing our established PAC-seq approach and PolyAMiner bioinformatic analysis pipeline, we deciphered the NUDT21-mediated differential APA dynamics in glioma cells. Results: We identified LAMC1 as a critical NUDT21 alternative polyadenylation (APA) target, common in several core glioma-driving signaling pathways. qRT-PCR analysis confirmed that NUDT21-knockdown in glioma cells results in the preferred usage of the proximal polyA signal (PAS) of LAMC1. Functional studies revealed that NUDT21-knockdown-induced 3'UTR shortening of LAMC1 is sufficient to cause translational gain, as LAMC1 protein is upregulated in these cells compared to their respective controls. We demonstrate that 3'UTR shortening of LAMC1 after NUDT21 knockdown removes binding sites for miR-124/506, thereby relieving potent miRNA-based repression of LAMC1 expression. Remarkably, we report that the knockdown of NUDT21 significantly promoted glioma cell migration and that co-depletion of LAMC1 with NUDT21 abolished this effect. Lastly, we observed that LAMC1 3'UTR shortening predicts poor prognosis of low-grade glioma patients from The Cancer Genome Atlas. This study identifies NUDT21 as a core alternative polyadenylation factor that regulates the tumor microenvironment through differential APA and loss of miR-124/506 inhibition of LAMC1. Knockdown of NUDT21 in GBM cells mediates 3'UTR shortening of LAMC1, contributing to an increase in LAMC1, increased glioma cell migration/invasion, and a poor prognosis.