TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas

Abstract

BACKGROUND: Pituitary adenomas (PAs) are common intracranial tumors and the TRIM family plays a crucial role in cell proliferation and therapeutic resistance of tumors. However, the role of the TRIM family in PAs is not well recognized. METHODS: CRISPR screening explored the role of the TRIM family in cell proliferation and drug resistance in PAs. In vitro and in vivo experiments were performed to evaluate the effects of Tripartite Motif Containing 21 (TRIM21). RNA-sequencing, mass spectrometry, immunoprecipitation, and ubiquitination experiments were performed to explore the molecular mechanism. NanoBiT assays were used to screen the drugs reducing TRIM21 expression. RESULTS: CRISPR-Cas9 screens identified that TRIM21 facilitated cell proliferation and drug resistance in PAs. Mechanistically, TRIM21 interacted with ERK1/2 through PRY-SPRY domain, leading to ERK1/2 K27-linked ubiquitination. The ERK1/2 ubiquitination promotes the interaction between ERK1/2 and MEK1/2, thereby facilitating the phosphorylation of ERK1/2. However, an excess presence of TRIM21 suppressed the phosphorylation of ERK1/2 and cell proliferation via activating ERK1/2 negative feedback pathways. Importantly, TRIM21 was upregulated in dopamine-resistant prolactinomas and cabergoline-resistant MMQ cells. Furthermore, drug screening identified that Fimepinostat and Quisinostat, can reduce the protein levels of TRIM21, inhibit tumor progression, and increase drug sensitivity. CONCLUSIONS: TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.