Dysfunction of the circadian transcriptional factor CLOCK in mice resists chemical carcinogen-induced tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Chronobiology

Background:

• Chronic disruption of circadian rhythms is linked to increased cancer risk.
• The CLOCK gene is a key component of the molecular circadian clock.
• Mutations in Clock (Clk/Clk) mice lead to abnormal physiological rhythms.

Purpose of the Study:

• To investigate the role of the CLOCK gene in chemical carcinogen-induced tumorigenesis.
• To determine if Clock gene mutations affect cancer development pathways.
• To explore potential preventive strategies targeting the CLOCK pathway.

Main Methods:

• Utilized a mouse model with a mutated Clock gene (Clk/Clk mice).
• Administered 7,12-dimethylbenz[α]anthracene (DMBA) to induce skin tumors.
• Assessed DMBA-induced DNA damage, epidermal growth factor receptor (EGFR) signaling, and cellular senescence markers (p16INK4a).

Main Results:

• Clk/Clk mice showed resistance to DMBA-induced tumorigenesis compared to wild-type mice.
• No significant difference in DMBA-induced DNA damage was observed between genotypes.
• EGFR-mediated Ras activation was suppressed in DMBA-treated Clk/Clk mice, linked to p16INK4a expression.

Conclusions:

• The CLOCK gene plays a previously unrecognized role in chemical carcinogen-induced primary tumor development.
• Suppression of EGFR signaling and induction of cellular senescence are mechanisms underlying this resistance.
• CLOCK may represent a novel target for cancer prevention strategies.