WIP1 is a novel specific target for growth hormone action

Area of Science:

• Molecular biology
• Cellular signaling
• Cancer research

Background:

• DNA damage repair (DDR) is crucial for maintaining genomic stability.
• ATM kinase, CHK2, p53, and γH2AX are key effectors in DDR pathways.
• Previous work indicated that growth hormone (GH) suppresses DDR by inhibiting pATM, leading to DNA damage accumulation.

Purpose of the Study:

• To elucidate the mechanism by which GH suppresses DNA damage repair.
• To identify specific molecular targets involved in GH-mediated DDR suppression.
• To explore the role of WIP1 in GH signaling and its impact on DNA damage.

Main Methods:

• Investigated GH signaling through the GH receptor (GHR) in human colon cells and intestinal organoids.
• Utilized mouse xenograft models with GH-secreting tumors and GHR knockout mice.
• Analyzed WIP1 induction, ATM phosphorylation, and DNA damage markers (pATM, γH2AX).
• Elucidated the signaling pathway involving Src, AMPK, and HIPK2 in regulating WIP1.
• Assessed the effect of WIP1 inhibition on ATM phosphorylation and DNA damage.

Main Results:

• GH induces wild-type p53-inducible phosphatase 1 (WIP1) via the GHR, which dephosphorylates ATM and its effectors.
• WIP1 was induced in mice with GH-secreting xenografts and patients with somatotroph adenomas, correlating with suppressed pATM and γH2AX.
• Conversely, colon WIP1 was decreased in GHR knockout mice.
• WIP1 inhibition restored ATM phosphorylation and reversed GH-induced DNA damage.
• A novel GH signaling pathway activating Src/AMPK was identified, leading to HIPK2 relocation and suppressed WIP1 ubiquitination.

Conclusions:

• GH promotes DNA damage accumulation by inducing WIP1, a phosphatase that deactivates key DDR kinases.
• The GH-GHR-WIP1 axis represents a novel pathway contributing to genomic instability.
• WIP1 is a specific molecular target for GH-mediated epithelial DNA damage, suggesting its potential as a therapeutic target.