The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regulator of the Oncogenic Nucleophosmin-MYC Axis

The transcriptional factor MYC and the nucleophosphoprotein nucleophosmin (NPM) act in concert to regulate the proliferation of both normal and cancer cells. MYC directly interacts with NPM to form an NPM-MYC binary complex, which is recruited to the promoter of MYC target genes to induce the transcription of proteins required for transformation, thus forming an oncogenic NPM-MYC axis. However, the regulatory molecules and mechanisms that control the transcription of MYC target genes by NPM remain to be determined. Herein, we describe a novel function of the nucleolar protein glioblastoma tumor-suppressive candidate region gene 2 (GLTSCR2) in regulating the transcriptional activity of MYC through an NPM-dependent pathway in SK-BR3 breast cancer cells. GLTSCR2 bound to NPM weakly in the nucleolus, but the redistribution of GLTSCR2 to the nucleoplasm increased the binding affinity between the two proteins. Enhancing the GLTSCR2-NPM interaction competitively inhibited the formation of the NPM-MYC binary complex, resulting in a decrease in the recruitment of the NPM-MYC complex to the MYC target gene promoter. This process suppressed the transcriptional and transformational activities of MYC. Thus, our data demonstrated that GLTSCR2 was an upstream negative regulator of the NPM-MYC axis involved in controlling the transcriptional activity of MYC, thereby suggesting that GLTSCR2 may be a novel candidate molecule for suppressing the growth of cancer cells stimulated by MYC hyperactivation.