MYC-Mediated Inhibition of ARNT2 Uncovers a Key Tumor Suppressor in Glioblastoma

TL;DR

This study identifies ARNT2 as a tumor suppressor in glioblastoma, showing that its inhibition by the MYC oncogene promotes cancer growth by limiting differentiation.

Contribution

The paper reveals a novel mechanism where MYC represses ARNT2 via PRC2, linking this repression to glioblastoma progression and establishing ARNT2 as a tumor suppressor.

Findings

ARNT2 is diminished in glioblastoma and inversely correlates with patient survival.

ARNT2 overexpression reduces glioblastoma cell growth in mouse models.

ARNT2 depletion increases stemness and reduces differentiation in glioblastoma cells.

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.