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 dif-ferentiation. 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.
|Number of pages||15|
|State||Published - 2017|
Bibliographical noteFunding Information:
Bin Wang for providing useful technical advice and helpful comments on this manuscript. The authors thank Dr. Edmund K. Waller and Dr. Ernestine A. Mahar for advice and guidance in flow cytometry using BD Canto II and Aria instruments. The authors also thank Department of Pediatrics Flow Cytometer Core, the Winship Cancer Tissue and Pathology Shared Resource, and the Integrated Cellular Imaging Shared Resource. 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).
© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
- stem cell
ASJC Scopus subject areas
- Molecular Medicine
- Cancer Research