TRIM 8 regulates stemness in glioblastoma through PIAS 3‐ STAT 3

Glioblastoma ( GBM ) is the most malignant form of primary brain tumor, and GBM stem‐like cells ( GSC s) contribute to the rapid growth, therapeutic resistance, and clinical recurrence of these fatal tumors. STAT 3 signaling supports the maintenance and proliferation of GSC s, yet regulatory mechanisms are not completely understood. Here, we report that tri‐partite motif‐containing protein 8 ( TRIM 8) activates STAT 3 signaling to maintain stemness and self‐renewing capabilities of GSC s. TRIM 8 (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 GBM s, and its expression is highly correlated with stem cell markers. Experimental knockdown of TRIM 8 reduced GSC self‐renewal and expression of SOX 2, NESTIN , and p‐ STAT 3, and promoted glial differentiation. Overexpression of TRIM 8 led to higher expression of p‐ STAT 3, c‐ MYC , SOX 2, NESTIN , and CD 133, and enhanced GSC self‐renewal. We found that TRIM 8 activates STAT 3 by suppressing the expression of PIAS 3, an inhibitor of STAT 3, most likely through E3‐mediated ubiquitination and proteasomal degradation. Interestingly, we also found that STAT 3 activation upregulates TRIM 8, providing a mechanism for normalized TRIM 8 expression in the setting of hemizygous gene deletion. These data demonstrate that bidirectional TRIM 8‐ STAT 3 signaling regulates stemness in GSC .