SRSF6 modulates histone-chaperone HIRA splicing to orchestrate AR and E2F activity in prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Advanced-stage prostate cancer (PCa) remains a lethal disease with unmet therapeutic needs.
• Splicing factor dysregulation is a cancer hallmark, but specific roles in PCa are often unknown.
• SRSF6's role in PCa pathogenesis requires detailed characterization.

Purpose of the Study:

• To investigate the expression levels and functional significance of SRSF6 in prostate cancer.
• To elucidate the molecular mechanisms by which SRSF6 influences PCa progression.
• To evaluate SRSF6 as a potential therapeutic target for advanced PCa.

Main Methods:

• Analysis of SRSF6 alterations (copy number, mRNA, protein) in multiple PCa cohorts and a transgenic model.
• In vitro functional assays (proliferation, migration, colony/tumorsphere formation) and in vivo xenograft studies.
• Mechanistic studies involving SRSF6's regulation of HIRA splicing and its impact on H3.3 activity and oncogenic pathways (AR, E2F).

Main Results:

• SRSF6 is significantly upregulated in PCa tissues and correlates with adverse clinical parameters.
• Modulation of SRSF6 impacts key cancer hallmarks, including proliferation, migration, and tumor growth.
• SRSF6 regulates HIRA splicing, affecting H3.3 activity and disrupting AR and E2F pathways in PCa.

Conclusions:

• SRSF6 is a key driver of prostate cancer progression and a potential therapeutic target.
• Understanding SRSF6-mediated splicing alterations provides insights into PCa pathogenesis.
• Targeting SRSF6 may offer a novel strategy for treating advanced-stage prostate cancer.