ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study assessed the effect of growth hormone (GH) on WIP1 (wild-type p53-inducible phosphatase 1), a key mediator of the DNA damage response (DDR). GH suppressed DDR by inducing WIP1, which dephosphorylates and inactivates ATM (ataxia-telangiectasia mutated) kinase and its downstream effectors (such as CHK2, p53 and H2AX), leading to the accumulation of unrepaired DNA, which can potentially contribute to tumorigenesis.

This elegant study demonstrates that GH, through its receptor (GHR), is able to induce the production of WIP1, a phosphatase that dephosphorylates ATM and its effectors (CHK2, p53 and H2AX), in human colon cells and intestinal organoids. WIP1 was also elevated in patients with high GH levels due to somatotrophic adenomas, whereas it was decreased in GHR-deficient mice. Inhibition of WIP1 restored ATM phosphorylation and reversed DNA damage. A novel GH signalling pathway involving Src/AMPK and HIPK2 prevents WIP1 degradation. GH is able to induce WIP1 in human colon cells, intestinal organoids and mammary cells, leading to a reduction in ATM phosphorylation and subsequent accumulation of damaged DNA. GH activates the Src/AMPK pathway, which triggers the translocation of HIPK2 from the nucleus to the cytoplasm. This translocation reduces the ability of HIPK2 to ubiquitinate and degrade WIP1, thereby stabilising WIP1 and increasing its phosphatase activity.

These results suggest that GH-induced WIP1 activity could contribute to a pro-tumorigenic environment by enabling the accumulation of damaged DNA, particularly in epithelial cells. This mechanism may explain the increased risk of neoplasia observed in conditions associated with elevated GH levels, such as acromegaly. By identifying WIP1 as a mediator of the suppressive effects of GH on DDR, the study paves the way for new therapeutic interventions targeting the GH/WIP1 axis to prevent or treat certain types of cancer.

References: 1. Schiewer, M.J., and Knudsen, K.E. (2016). Linking DNA Damage and Hormone Signaling Pathways in Cancer. Trends Endocrinol. Metab. 27, 216–225.2. Chesnokova, V., and Melmed, S. (2020). Peptide Hormone Regulation of DNA Damage Responses. Endocr. Rev. 41, bnaa009.3. Chesnokova, V., Zonis, S., Barrett, R., Kameda, H., Wawrowsky, K., Ben-Shlomo, A., Yamamoto, M., Gleeson, J., Bresee, C., Gorbunova, V., and Melmed, S. (2019). Excess growth hormone suppresses DNA damage repair in epithelial cells. JCI Insight 4, e125762.