Oncogenic translation directs spliceosome dynamics revealing an integral role for SF3A3 in breast cancer

Area of Science:

• Molecular Biology
• Cancer Research
• RNA Biology

Background:

• Splicing is crucial in RNA processing and frequently altered in cancers.
• The precise mechanisms by which spliceosomal components contribute to tumorigenesis are not fully understood.

Purpose of the Study:

• To investigate the role of the core splice factor SF3A3 in cancer development.
• To elucidate the interplay between splicing and translation in MYC-driven oncogenesis.

Main Methods:

• Analysis of SF3A3 modulation during malignant transformation.
• Investigating the translational control of SF3A3 via RNA stem-loops and eIF3D.
• Assessing the impact of altered SF3A3 on mRNA splicing, particularly for mitochondrial regulators.
• Evaluating the functional consequences of altered SF3A3 translation on cellular metabolism and stem-like properties in vivo.
• Correlating SF3A3 protein levels with aggressive breast cancer features.

Main Results:

• SF3A3 levels are translationally regulated by an RNA stem-loop in an eIF3D-dependent manner upon MYC hyperactivation.
• This regulation ensures proper splicing of mRNAs encoding mitochondrial regulators.
• Dysregulated SF3A3 translation promotes metabolic reprogramming and stem-like characteristics, supporting MYC-driven tumorigenesis.
• SF3A3 protein levels serve as a biomarker for aggressive human breast cancers.

Conclusions:

• SF3A3 acts as a key mediator linking translation and splicing in MYC-driven cancers.
• The findings highlight a novel post-transcriptional regulatory network critical for oncogenesis.
• SF3A3 represents a potential therapeutic target in aggressive breast cancers.