SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1

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Abstract

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 ( MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

Abstract

SF3A2 up-regulation in TNBC regulates MKRN1 alternative splicing switching, leading to cancer progression and cisplatin resistance.

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Most cited references 57

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rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data.

Shihao Shen, Juw Won Park, Zhi-xiang Lu … (2014)

Ultra-deep RNA sequencing (RNA-Seq) has become a powerful approach for genome-wide analysis of pre-mRNA alternative splicing. We previously developed multivariate analysis of transcript splicing (MATS), a statistical method for detecting differential alternative splicing between two RNA-Seq samples. Here we describe a new statistical model and computer program, replicate MATS (rMATS), designed for detection of differential alternative splicing from replicate RNA-Seq data. rMATS uses a hierarchical model to simultaneously account for sampling uncertainty in individual replicates and variability among replicates. In addition to the analysis of unpaired replicates, rMATS also includes a model specifically designed for paired replicates between sample groups. The hypothesis-testing framework of rMATS is flexible and can assess the statistical significance over any user-defined magnitude of splicing change. The performance of rMATS is evaluated by the analysis of simulated and real RNA-Seq data. rMATS outperformed two existing methods for replicate RNA-Seq data in all simulation settings, and RT-PCR yielded a high validation rate (94%) in an RNA-Seq dataset of prostate cancer cell lines. Our data also provide guiding principles for designing RNA-Seq studies of alternative splicing. We demonstrate that it is essential to incorporate biological replicates in the study design. Of note, pooling RNAs or merging RNA-Seq data from multiple replicates is not an effective approach to account for variability, and the result is particularly sensitive to outliers. The rMATS source code is freely available at rnaseq-mats.sourceforge.net/. As the popularity of RNA-Seq continues to grow, we expect rMATS will be useful for studies of alternative splicing in diverse RNA-Seq projects.

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Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.

Giampaolo Bianchini, Justin Balko, Ingrid Mayer … (2016)

Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.

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Targeting apoptosis in cancer therapy

Benedito A Carneiro, Wafik El-Deiry (2020)

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Author and article information

Contributors

Ling Deng:

ORCID: https://orcid.org/0000-0001-5237-781X

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Li Liao:

ORCID: https://orcid.org/0000-0002-6651-0033

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization

Yin-Ling Zhang:

ORCID: https://orcid.org/0009-0008-2581-6387

Role: Data curationRole: Formal analysisRole: InvestigationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Shao-Ying Yang: Role: Formal analysisRole: Software

Shu-Yuan Hu:

ORCID: https://orcid.org/0000-0002-2521-7949

Role: InvestigationRole: ResourcesRole: Validation

Lisa Andriani: Role: Investigation

Yun-Xiao Ling: Role: Formal analysisRole: Software

Xiao-Yan Ma: Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing - original draft

Fang-Lin Zhang:

ORCID: https://orcid.org/0000-0002-5728-0272

Role: ConceptualizationRole: Funding acquisitionRole: Methodology

Zhi-Ming Shao: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Da-Qiang Li:

ORCID: https://orcid.org/0000-0002-5113-2332

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: 05 April 2024

Publication date (Electronic, pub): 03 April 2024

Volume: 10

Issue: 14

Electronic Location Identifier: eadj4009

Affiliations

[ ¹ ]Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.

[ ² ]Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China.

[ ³ ]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

[ ⁴ ]Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai 200032, China.

[ ⁵ ]Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai 200032, China.

[ ⁶ ]Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Author notes

[* ]Corresponding author. Email: zhangfanglin555@ 123456sina.com (F.-L.Z.); zhimingshao@ 123456fudan.edu.cn (Z.-M.S); daqiangli1974@ 123456fudan.edu.cn (D.-Q.L.)

[†]

These authors contributed equally to the work.

Author information

Ling Deng https://orcid.org/0000-0001-5237-781X

Li Liao https://orcid.org/0000-0002-6651-0033

Yin-Ling Zhang https://orcid.org/0009-0008-2581-6387

Shu-Yuan Hu https://orcid.org/0000-0002-2521-7949

Fang-Lin Zhang https://orcid.org/0000-0002-5728-0272

Da-Qiang Li https://orcid.org/0000-0002-5113-2332

Article

Publisher ID: adj4009

DOI: 10.1126/sciadv.adj4009

PMC ID: 10990288

PubMed ID: 38569025

SO-VID: 68e97a77-d39e-4291-8554-4e8517a6fcd5

Copyright © Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 25 June 2023

Date accepted : 28 February 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100007219, Natural Science Foundation of Shanghai;

Award ID: 22ZR1413100

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81772805

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81972461

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82173275

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82072918

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SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1

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Most cited references 57

rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data.

Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease.

Targeting apoptosis in cancer therapy

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