Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth

Area of Science:

• Molecular Biology
• Cancer Biology
• Chronobiology

Background:

• Circadian clock disruption is associated with cancer development.
• The interaction between oncogenic receptor tyrosine kinases and the circadian clock is not well understood.

Purpose of the Study:

• To investigate how receptor tyrosine kinases modulate the circadian clock in hepatocellular carcinoma (HCC).
• To elucidate the molecular mechanisms linking circadian clock dysfunction to HCC progression.

Main Methods:

• Utilized hepatocellular carcinoma (HCC) cell lines.
• Investigated CLOCK protein phosphorylation and its interaction with BMAL1.
• Examined the role of Exportin1 in CLOCK nuclear export.
• Analyzed the acetylation of PRPS1/2 and its effect on protein degradation.
• Correlated CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation with human HCC specimens.

Main Results:

• Receptor tyrosine kinase activation leads to CK2-mediated CLOCK S106 phosphorylation, disrupting the CLOCK-BMAL1 dimer and downregulating gene expression in HCC cells.
• Phosphorylated CLOCK is exported from the nucleus, where it acetylates PRPS1/2 at K29.
• Stabilized PRPS1/2 promotes nucleotide synthesis, enhancing HCC cell proliferation and liver tumor growth.
• CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation correlate with poor HCC prognosis.

Conclusions:

• Oncogenic signaling inhibits the canonical transcriptional activity of the CLOCK protein.
• CLOCK protein acquires moonlighting functions to promote nucleotide synthesis and tumor growth in HCC.
• CLOCK S106 phosphorylation is a critical event linking oncogenic signaling to circadian clock disruption and HCC progression.