Nuclear S6K1 Enhances Oncogenic Wnt Signaling by Inducing Wnt/β-Catenin Transcriptional Complex Formation

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• Ribosomal protein S6 kinase 1 (S6K1), downstream of mTOR, regulates cell growth and protein synthesis.
• Previously, S6K1 was primarily studied in the cytoplasm, but recent findings indicate nuclear functions.
• The precise nuclear roles of S6K1, particularly in signaling pathways, are still being uncovered.

Purpose of the Study:

• To investigate the novel nuclear role of S6K1 in regulating Wnt target gene expression.
• To elucidate the mechanism by which S6K1 influences the Wnt/β-catenin transcriptional complex.
• To assess the impact of S6K1 on colon cancer cell behavior.

Main Methods:

• Utilized Wnt signaling activation to observe S6K1 translocation.
• Investigated S6K1 binding to β-catenin and transcriptional cofactors.
• Employed S6K1 depletion/repression in colon cancer cell lines.
• Analyzed Wnt target gene expression, cell proliferation, and invasion levels.

Main Results:

• Upon Wnt signaling activation, S6K1 translocated to the nucleus.
• Nuclear S6K1 bound to β-catenin and cofactors, upregulating Wnt target genes.
• S6K1 depletion inhibited Wnt/β-catenin complex formation and target gene expression.
• S6K1-depleted colon cancer cells exhibited reduced proliferation and invasion.

Conclusions:

• Nuclear S6K1 plays a positive regulatory role in Wnt target gene expression.
• S6K1 enhances Wnt/β-catenin transcriptional complex activity through subunit interactions.
• Targeting nuclear S6K1 may offer a therapeutic strategy for colon cancer.