Abstract
Tripartite motif-containing protein 45 (TRIM45) belongs to a large family of RING-finger-containing E3 ligases, which are highly expressed in the brain. However, little is known regarding the role of TRIM45 in cancer biology, especially in human glioma. Here, we report that TRIM45 expression is significantly reduced in glioma tissue samples. Overexpression of TRIM45 suppresses proliferation and tumorigenicity in glioblastoma cells in vitro and in vivo. In addition, CRISPR/Cas9-mediated knockout of TRIM45 promotes proliferation and inhibits apoptosis in glioblastoma cells. Further mechanistic analyses show that TRIM45 interacts with and stabilizes p53. TRIM45 conjugates K63-linked polyubiquitin chain to the C-terminal six lysine residues of p53, thereby inhibiting the availability of these residues to the K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 is a novel tumor suppressor that stabilizes and activates p53 in glioma.
Highlights
Gliomas are the most common type of brain tumors and account for ~ 80% of primary malignant tumors in the central nervous system (CNS).[1,2,3] Currently, the standard treatment strategies for glioma are surgical resection and adjuvant chemotherapy with temozolomide (TMZ) combined with radiotherapy.[4]
We subsequently investigated whether TRIM45 expression levels represented a distinct molecular signature for a subset of gliomas
TRIM45 mRNA levels were lower in high-grade (WHO grade III/IV) gliomas compared with lowgrade (WHO grade I/II) gliomas (Figure 1c)
Summary
Gliomas are the most common type of brain tumors and account for ~ 80% of primary malignant tumors in the central nervous system (CNS).[1,2,3] Currently, the standard treatment strategies for glioma are surgical resection and adjuvant chemotherapy with temozolomide (TMZ) combined with radiotherapy.[4]. Ubiquitination is a reversible post-translational modification that either targets proteins for degradation or regulates protein function.[10] Ubiquitin itself contains seven lysines, and each of these can be further conjugated to another ubiquitin molecule at its carboxyl terminus to form different types of polyubiquitin chains. The lysine-(K) 48- and K63-linked polyubiquitin chains are the predominant types of ubiquitin linkage.[11] K48-linked polyubiquitination targets proteins for proteasomal degradation, and K63-linked polyubiquitination has a role in cell signaling. TRIM45 interacts with and stabilizes p53 by promoting K63-linked polyubiquitination of p53, thereby inhibiting the subsequent K48-linked polyubiquitination that targets p53 for degradation. These findings suggest that TRIM45 functions as a novel regulator responsible for maintaining p53 stability in glioma
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