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PTf-SRiApt Targeting SCAF4-POLR2A Interaction Suppresses Tumor Growth and Promotes Antitumor Immunity in
Liyan Fei1,2, Yichun Pan2, Jie Zhai3,2
1School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, 230026, P. R. China.
Abstract:
The interaction between SCAF4 and RNA polymerase II (POLR2A) is crucial for proper mRNA termination, with its dysregulation leading to truncated mRNAs and nonfunctional proteins, impairing cellular growth. Despite its potential relevance, the role of this interaction in triple-negative breast cancer (TNBC) remains unexplored due to the lack of effective molecular tools. To address this, we employed SRiApt, an aptamer generated through the recently established Blocker-SELEX pipeline. Its biological stability is improved by phosphorothioate modifications to form PTf-SRiApt. Using this aptamer, the critical role of the SCAF4-POLR2A interaction in driving TNBC tumor growth and immune regulation is uncovered. PTf-SRiApt effectively inhibits tumor growth and induces cell cycle arrest in TNBC cells with elevated SCAF4 and POLR2A expression. Additionally, PTf-SRiApt promotes premature mRNA termination, boosting antigen presentation and promoting T-cell infiltration. Analysis of patient samples further confirmed the negative correlation between SCAF4-POLR2A interaction and the effectiveness of immunotherapy, highlighting the potential of PTf-SRiApt in improving immune efficacy. Together, the work provides a powerful tool not only for dissecting previously "undruggable" protein-protein interactions but also for enhancing tumor immunogenicity and reshaping the tumor microenvironment.
Insights
A novel aptamer, PTf-SRiApt, targets the SCAF4-POLR2A interaction, inhibiting triple-negative breast cancer (TNBC) growth and enhancing anti-tumor immunity. This tool aids in understanding previously undruggable targets and improving immunotherapy efficacy.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- The SCAF4-RNA polymerase II (POLR2A) interaction is vital for mRNA termination, and its disruption impairs cellular growth.
- Dysregulation of this interaction is implicated in diseases, but its role in triple-negative breast cancer (TNBC) is unknown due to limited molecular tools.
Purpose of the Study:
- To investigate the role of the SCAF4-POLR2A interaction in TNBC progression and immune evasion.
- To develop and utilize a novel aptamer tool for studying this interaction in TNBC.
Main Methods:
- Generation of a modified aptamer, PTf-SRiApt, with enhanced stability.
- Application of PTf-SRiApt to inhibit SCAF4-POLR2A interaction in TNBC cells.
- Assessment of PTf-SRiApt's effects on tumor growth, cell cycle, mRNA termination, and immune cell infiltration.
- Analysis of patient samples to correlate SCAF4-POLR2A interaction with immunotherapy outcomes.
Main Results:
- PTf-SRiApt effectively inhibits TNBC tumor growth and induces cell cycle arrest in cells with high SCAF4 and POLR2A expression.
- The aptamer promotes premature mRNA termination, enhancing antigen presentation and T-cell infiltration.
- Patient data reveals a negative correlation between SCAF4-POLR2A interaction and immunotherapy effectiveness.
Conclusions:
- The SCAF4-POLR2A interaction is a critical driver of TNBC growth and immune suppression.
- PTf-SRiApt is a potent tool for dissecting "undruggable" protein-protein interactions and offers therapeutic potential.
- Targeting SCAF4-POLR2A interaction can enhance anti-tumor immunity and improve immunotherapy outcomes in TNBC.
