An In Vivo CRISPR Screen Identifies That SNRPC Promotes Triple-Negative Breast Cancer Progression

Author:

Lu Xun-Xi1234ORCID,Yang Wen-Xiao1234ORCID,Pei Yu-Chen1ORCID,Luo Hong1ORCID,Li Xiao-Guang1ORCID,Wang Yun-Jin1ORCID,Zhang Guo-Liang1ORCID,Ling Hong2ORCID,Shao Zhi-Ming123ORCID,Hu Xin123ORCID

Affiliation:

1. 1Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China.

2. 2Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

3. 3Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.

4. 4Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Abstract

Abstract Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomarkers and treatment strategies. To identify oncogenic RBPs in triple-negative breast cancer (TNBC), we employed an in vivo CRISPR screen and a TNBC progression model, which revealed small nuclear ribonucleoprotein polypeptide C (SNRPC), a subunit of the U1 small nuclear ribonucleoprotein particle (U1 snRNP), as a key modulator of TNBC progression. SNRPC was frequently upregulated, which corresponded to poor prognosis in patients with TNBC. SNRPC ablation significantly impaired the proliferation, migration, and invasion of TNBC cells in vitro and in vivo. In addition, SNRPC was essential for the stability of U1 snRNP and contributed to the RNA Pol II–controlled transcriptional program. Knockdown of SNRPC decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, and CDK4) and reduced their expression levels. Furthermore, SNRPC deletion was confirmed to inhibit TNBC progression partially through regulation of the TNFAIP2-Rac1–β-catenin signaling pathway. Taken together, this data suggests that SNRPC plays an oncogenic role in TNBC, is a marker of poor prognosis, and may be a valuable therapeutic target for patients with intractable TNBC. Significance: A functional CRISPR screen identifies SNRPC as an RNA-binding protein that promotes the aggressiveness of breast cancer by facilitating Pol II–controlled transcription of oncogenes.

Funder

National Natural Science Foundation of China

Shanghai Science and Technology Innovation Action Plan

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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