
==== Front
Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184078
10.21203/rs.3.rs-4810280/v1
10.21203/rs.3.rs-4810280
preprint
1
Article
MYC-Mediated Inhibition of ARNT2 Uncovers a Key Tumor Suppressor in Glioblastoma
Hao Yi-Heng
Borenstein-Auerbach Nofit
Grichuk Anthony
Li Li
Lafita-Navarro M. Carmen
Fang Shun
Nogueira Pedro
Kim Jiwoong
Xu Lin
Shay Jerry W. https://orcid.org/0000-0001-5052-0627

Conacci-Sorrell Maralice
15 8 2024
rs.3.rs-4810280https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4810280/v1
nihpp-rs4810280v1.pdf
Abstract

Tumor initiation and progression rely on intricate cellular pathways that promote proliferation while suppressing differentiation, yet the importance of pathways inhibiting differentiation in cancer remains incompletely understood. Here, we reveal a novel mechanism centered on the repression of the neuronal-specific transcription factor ARNT2 by the MYC oncogene that governs the balance between proliferation and differentiation. We found that MYC coordinates the transcriptional repression of ARNT2 through the activity of polycomb repressive complex 2 (PRC2). Notably, ARNT2, highly and specifically expressed in the central nervous system, is diminished in glioblastoma, inversely correlating with patient survival. Utilizing in vitro and in vivo models, we demonstrate that ARNT2 knockout (KO) exerts no discernible effect on the in vitro proliferation of glioblastoma cells, but significantly enhances the growth of glioblastoma cells in vivo. Conversely, ARNT2 overexpression severely dampens the growth of fully transformed glioblastoma cells subcutaneously or orthotopically xenografted in mice. Mechanistically, ARNT2 depletion diminishes differentiation and enhances stemness of glioblastoma cells. Our findings provide new insights into the complex mechanisms used by oncogenes to limit differentiation in cancer cells and define ARNT2 as a tumor suppressor in glioblastoma.
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