TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3

• Type of Material: Article
• Authors: Changming Zhang, Emory University; Subhas Mukherjee, Emory University; Carol Tucker-Burden, Emory University; James L. Ross, Emory University; Monica J. Chau, Emory University; Jun Kong, Emory University; Daniel Brat, Emory University
• Language: English
• Date: 2017-03-01
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/1878-0261.12034
• Title of Journal or Parent Work: Molecular Oncology
• ISSN: 1574-7891
• Volume: 11
• Issue: 3
• Start Page: 280
• End Page: 294
• Grant/Funding Information: This work was supported by US Public Health Service National Institutes of Health (NIH) Grants R01 CA176659 (DJB), CA149107 (DJB), and K25CA181503 (JK); the Winship Cancer Institute NCI Cancer Center Support Grant P30CA138292; and the Georgia Research Alliance (DJB).
• Keywords: ORTHOLOG TRIM3; Life Sciences & Biomedicine; NUCLEAR TRANSLOCATION; PIAS3; STAT3; TRIM8; CELL MAINTENANCE; Oncology; NEGATIVE REGULATION; GLIOMA; MODULATES STAT3 ACTIVITY; SELF-RENEWAL; stem cell; GENE-EXPRESSION; glioblastoma; Science & Technology; PROTEIN; CANCER-CELLS
• Research Categories: Health Sciences, General; Health Sciences, Oncology

Abstract

Glioblastoma (GBM) is the most malignant form of primary brain tumor, and GBM stem-like cells (GSCs) contribute to the rapid growth, therapeutic resistance, and clinical recurrence of these fatal tumors. STAT3 signaling supports the maintenance and proliferation of GSCs, yet regulatory mechanisms are not completely understood. Here, we report that tri-partite motif-containing protein 8 (TRIM8) activates STAT3 signaling to maintain stemness and self-renewing capabilities of GSCs. TRIM8 (also known as 'glioblastoma-expressed ring finger protein') is expressed equally in GBM and normal brain tissues, despite its hemizygous deletion in the large majority of GBMs, and its expression is highly correlated with stem cell markers. Experimental knockdown of TRIM8 reduced GSC self-renewal and expression of SOX2, NESTIN, and p-STAT3, and promoted glial differentiation. Overexpression of TRIM8 led to higher expression of p-STAT3, c-MYC, SOX2, NESTIN, and CD133, and enhanced GSC self-renewal. We found that TRIM8 activates STAT3 by suppressing the expression of PIAS3, an inhibitor of STAT3, most likely through E3-mediated ubiquitination and proteasomal degradation. Interestingly, we also found that STAT3 activation upregulates TRIM8, providing a mechanism for normalized TRIM8 expression in the setting of hemizygous gene deletion. These data demonstrate that bidirectional TRIM8-STAT3 signaling regulates stemness in GSC.