Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Arginine is a semi-essential amino acid crucial for cellular functions.
• Arginine deprivation targets cancers lacking arginine synthesis, causing mitochondrial dysfunction and cell death.
• Prostate cancer cells' response to arginine deprivation requires further elucidation.

Purpose of the Study:

• To investigate arginine's role as an epigenetic regulator in prostate cancer.
• To determine the mechanism by which arginine influences oxidative phosphorylation (OXPHOS) gene expression.
• To evaluate the therapeutic potential of targeting TEAD4 in prostate cancer.

Main Methods:

• Analysis of histone acetylation and acetyl-CoA levels in arginine-modulated prostate cancer cells.
• Investigation of TEAD4 nuclear localization and promoter/enhancer binding activity.
• Assessment of OXPHOS gene expression and cellular functions upon TEAD4 manipulation.
• In vitro and in vivo studies evaluating the impact of TEAD4 silencing on prostate cancer growth.

Main Results:

• Arginine epigenetically upregulates nuclear-encoded OXPHOS genes via histone acetylation.
• Arginine promotes TEAD4 nuclear retention and recruitment to OXPHOS gene regulatory regions.
• TEAD4 upregulation is dependent on mammalian target of rapamycin (mTOR) but independent of YAP1.
• TEAD4 silencing inhibits OXPHOS and prostate cancer cell proliferation in vitro and in vivo.

Conclusions:

• Arginine functions as an epigenetic regulator, modulating histone acetylation and OXPHOS gene expression in prostate cancer.
• TEAD4 is a key mediator of arginine's effects on OXPHOS and prostate cancer cell growth.
• Targeting TEAD4 presents a potential strategy to enhance arginine-deprivation therapy and treat prostate cancer.