SOX2 downregulation of PML increases HCMV gene expression and growth of glioma cells

PLoS Pathog. 2023 Apr 14;19(4):e1011316. doi: 10.1371/journal.ppat.1011316. eCollection 2023 Apr.

Abstract

The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytomegalovirus / physiology
  • Down-Regulation
  • Gene Expression
  • Glioma* / genetics
  • Glioma* / pathology
  • Humans
  • Immediate-Early Proteins* / metabolism
  • Mice
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Immediate-Early Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Transcription Factors
  • PML protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China (82002128) and postdoctoral research funding from Guangzhou Women and Children’s Medical Center (011302012) to LW. (https://grants.nsfc.gov.cn/) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.