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

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2024-11-13 DOI:10.1093/neuonc/noae241

Yanting Liu, Fang Liu, Chuanbao Li, Tao Zhang, Tianyi Han, Yuting Dai, Ning Huang, Hao Tang, Xiaobin Wang, Shaojian Lin, Li Xue, Zhe Bao Wu

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引用次数: 0

Abstract

Background: Pituitary adenomas (PAs) are common intracranial tumors and 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 TRIM family in the 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 supressed 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.

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TRIM21 介导的泛素化和 ERK1/2 磷酸化促进了垂体腺瘤的细胞增殖和抗药性。

背景：垂体腺瘤（PAs）是常见的颅内肿瘤，TRIM家族在细胞增殖和肿瘤抗药性方面起着至关重要的作用。然而，TRIM家族在垂体腺瘤中的作用尚未得到充分认识：CRISPR筛选探索了TRIM家族在PAs细胞增殖和耐药性中的作用。方法：通过 CRISPR 筛选探讨 TRIM 家族在 PAs 细胞增殖和耐药性中的作用。为探索其分子机制，还进行了 RNA 序列测定、质谱分析、免疫沉淀和泛素化实验。结果：CRISPR-Cas9 筛选出了减少 TRIM21 表达的药物：结果：CRISPR-Cas9筛选发现，TRIM21促进了PAs的细胞增殖和耐药性。从机理上讲，TRIM21通过PRY-SPRY结构域与ERK1/2相互作用，导致ERK1/2 K27连接泛素化。ERK1/2泛素化促进了ERK1/2和MEK1/2之间的相互作用，从而促进了ERK1/2的磷酸化。然而，TRIM21的过量存在会通过激活ERK1/2负反馈途径抑制ERK1/2的磷酸化和细胞增殖。重要的是，TRIM21在多巴胺抗性催乳素瘤和卡麦角林抗性MMQ细胞中上调。此外，药物筛选发现，菲米诺司他和奎司他能降低TRIM21的蛋白水平，抑制肿瘤进展，并增加药物敏感性：结论：TRIM21可能是肿瘤的治疗靶点，抑制TRIM21可能是一种潜在的肿瘤治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.