Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mutant p53 (mtp53) functions as an oncogene, promoting cancer cell proliferation.
• The role of mtp53 in regulating cellular metabolism, particularly nucleotide biosynthesis, remains incompletely understood.

Purpose of the Study:

• To investigate the association of mtp53 with nucleotide metabolism genes (NMG).
• To elucidate the functional consequences of mtp53-mediated regulation of NMG on cancer cell behavior and identify potential therapeutic vulnerabilities.

Main Methods:

• Utilized gene knockdown techniques to assess the impact of mtp53 on NMG expression.
• Quantified nucleotide pools and measured GTP-dependent protein activity and cell invasion.
• Investigated the role of the nucleoside salvage pathway and deoxycytidine kinase in mtp53-harboring cells.
• Correlated NMG expression with mtp53 status and patient prognosis in breast cancer datasets.

Main Results:

• Mtp53 was found to associate with promoters of numerous NMG, and its knockdown reduced NMG expression and nucleotide pools.
• Depletion of nucleotides attenuated GTP-dependent activity and cell invasion, which could be restored by exogenous guanosine or GTP.
• Mtp53 induced a dependency on deoxycytidine kinase for maintaining dNTP pool balance, creating a synthetic sick/lethal phenotype with the salvage pathway.
• Elevated NMG expression correlated with mtp53 status and poor prognosis in breast cancer patients.

Conclusions:

• Mtp53 drives cancer proliferation and invasion by regulating nucleotide metabolism, particularly increasing GTP levels.
• Mtp53-harboring cells exhibit a dependency on the nucleoside salvage pathway, presenting a potential therapeutic target.
• The findings highlight mtp53's critical role in both initiating and sustaining cancer development through metabolic reprogramming.