Abstract
Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas-mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. ©2018 AACR.
Highlights
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death in women worldwide [1]
The primary tumors induced by CA1a cells grew faster than the tumors induced by DCIS cells (Fig. 1B, P 1⁄4 0.000002), and the CA1a cells formed more lung metastases than the DCIS cells (Fig. 1C, P 1⁄4 0.0014)
These cell lines are negative for hormone receptor and human epidermal growth factor receptor 2 (HER2) and are more likely to be characterized as exhibiting the basal-like subtype using the PAM50 classifier (Supplementary Fig. S1D and S1E)
Summary
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death in women worldwide [1]. Understanding the molecular underpinning of cancer progression is crucial for the development of effective strategies for treating this deadly disease. More than 90% of human genes produce transcripts that are alternatively spliced, and 60% of the splice variants encode distinct protein isoforms [2]. Aberrant splicing (AS) is common in cancer [3], and cancer cells often take advantage of this flexibility to produce proteins that promote tumor growth and. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). All the widely accepted hallmarks of cancer are known to be affected by aberrant splicing, and splicing dysregulation itself is considered one of the epigenetic hallmarks of cancer and a valuable therapeutic target [5,6,7]
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