SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA.

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2024-09-27 DOI:10.1111/cas.16356
Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun
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Abstract

Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.

SNRPB2通过控制MDM4前mRNA的替代剪接促进三阴性乳腺癌的进展。
交替剪接产生癌症特异性转录本,现已被公认为癌症的标志。然而,三阴性乳腺癌(TNBC)中涉及的关键致癌剪接体相关蛋白仍然难以确定。在这里,我们探讨了剪接体相关蛋白在TNBC、非TNBC和正常乳腺组织中的表达模式,发现近一半的剪接体相关蛋白在TNBC中的表达高于其同类组织。在这些TNBC特异性剪接体相关蛋白中,SNRPB2的表达与TNBC患者的不良预后有关。在TNBC细胞中,敲除SNRPB2可强烈抑制细胞增殖和侵袭,并诱导细胞周期停滞。从机理上讲,转录组数据显示,SNRPB2的敲除使E2F1信号失活,而E2F1信号调控细胞周期。我们进一步验证了 SNRPB2 敲除细胞中多个细胞周期基因的下调。此外,分析表明,SNRPB2敲除引发了许多替代剪接事件的改变,其中大部分是跳过外显子。在TNBC细胞中,研究发现SNRPB2敲除会导致MDM4前mRNA第6外显子的跳过,产生MDM4-S转录本,并下调MDM4蛋白的表达。更重要的是,MDM4的下调降低了视网膜母细胞瘤1(Rb1)蛋白的表达,而Rb1是MDM4的靶标,也是E2F1信号转导的调控因子。总之,本研究揭示了促进 TNBC 进展的 SNRPB2/MDM4/Rb 轴,为抗击 TNBC 提供了新的见解和新的靶点。
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
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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