Hippo pathway monomerizes STAT3 to regulate prostate cancer growth

Area of Science:

• Molecular Biology
• Oncology
• Cell Signaling

Background:

• Prostate cancer is a significant public health concern, with inflammation playing a role in its development.
• The Hippo pathway is crucial for regulating tissue homeostasis, but its role in cancer-related inflammation is unclear.

Purpose of the Study:

• To investigate the interplay between the Hippo pathway and inflammatory factors in prostate cancer.
• To determine if the Hippo pathway influences STAT3 activity, a key inflammatory signaling molecule.

Main Methods:

• Investigated the effect of high cell density on Hippo pathway activation and STAT3 activity in prostate cancer cells.
• Utilized molecular techniques to identify and characterize the phosphorylation of STAT3 by MST2 kinase.
• Employed a nonphosphorylatable STAT3 T622A mutant to assess its impact on STAT3 activity and tumor growth in vivo.

Main Results:

• High cell density activates the Hippo pathway, leading to MST2 kinase-mediated phosphorylation of STAT3 at T622.
• This phosphorylation inhibits STAT3 dimerization and IL6-induced activation, thereby blunting inflammatory signaling.
• A nonphosphorylatable STAT3 mutant (T622A) showed enhanced activity and promoted tumor growth in a mouse xenograft model.

Conclusions:

• STAT3 is identified as a novel phosphorylation substrate for MST2 kinase within the Hippo pathway.
• This study elucidates a regulatory cascade connecting the Hippo pathway and inflammation via STAT3 in prostate cancer.
• Findings highlight a potential therapeutic target for modulating inflammation and tumor progression in prostate cancer.