Dysregulated SASS6 expression promotes increased ciliogenesis and cell invasion phenotypes

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Biology

Background:

• Centriole and cilium defects are hallmarks of cancer, linked to invasion, but mechanisms are unclear.
• Spindle assembly abnormal protein 6 homolog (SAS-6) is crucial for centriole/cilium formation and normally degraded in late mitosis/G1.
• Uncontrolled SAS-6 expression's role in cancer progression requires further investigation.

Purpose of the Study:

• To investigate the mechanistic link between SAS-6, ciliogenesis, and cancer cell invasion.
• To determine the role of SAS-6 in regulating the YAP/TAZ pathway in cancer cells.
• To explore SAS-6 as a potential therapeutic target in invasive lung cancer.

Main Methods:

• Utilized a non-degradable SAS-6 mutant (SAS-6ND) to study its effects.
• Assessed cell morphology, ciliation, nuclear deformation, and YAP/TAZ pathway activation (including TEAD transcription).
• Employed gene down-regulation strategies for SAS-6 and YAP, and inhibited ciliogenesis in lung cancer cell lines.

Main Results:

• Non-degradable SAS-6 (SAS-6ND) increased ciliation, cell invasion, and YAP/TAZ pathway activation.
• SAS-6ND induced cell/nuclear shape changes and nuclear YAP translocation, enhancing TEAD-dependent transcription.
• Blocking SAS-6 in invasive lung cancer cells (DMS273) halted invasion and reduced YAP levels; YAP inhibition or blocking ciliogenesis also prevented SAS-6-mediated invasion.

Conclusions:

• SAS-6 directly promotes cancer cell invasion through YAP/TAZ pathway activation.
• SAS-6-induced ciliogenesis and YAP/TAZ signaling are critical for its pro-invasive effects.
• Targeting SAS-6 or YAP presents a potential strategy to combat invasive cancers.