The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense

Abstract

Only humans and higher primates have high uric acid blood levels. Although high uric acid causes gout, it has been linked with human longevity because of its hypothetical antioxidant function. Recent studies reveal that p53 has significant roles in cellular metabolism. One example of this is an antioxidant function that potentially contributes to tumor suppression. Here, we reported a first beneficial link between p53 and uric acid. We identified the uric acid transporter SLC2A9 (also known as GLUT9) as a direct p53 target gene and a key downstream effector in the reduction of reactive oxygen species (ROS) through transporting uric acid as a source of antioxidant. Oxidative stress induced SLC2A9 expression in a p53-dependent manner, and inhibition of SLC2A9 by small interfering RNA (siRNA) or anti-gout drugs such as probenecid significantly increased ROS levels in an uric acid-dependent manner and greatly sensitized cancer cells to chemotherapeutic drugs. Conversely, expression of SLC2A9 reduced ROS and protected against DNA damage and cell death, suggesting its antioxidant function. The increased production of ROS because of p53 loss was rescued by SLC2A9 expression. Furthermore, decreased SLC2A9 expression was observed in several cancer types and was associated with a poorer prognosis. Our findings suggest that the p53-SLC2A9 pathway is a novel antioxidant mechanism that uses uric acid to maintain ROS homeostasis and prevent accumulation of ROS-associated damage that potentially contributes to cancer development.

Discovery of unfixed endogenous retrovirus insertions in diverse human populations

“…For example, the 8q24.3c provirus is situated within COMMD5, a gene involved in hypertension-related renal repair whose expression is elevated in the kidneys of hypertensionresistant rat models (55). The 4p16d LTR, in ∼1.5% of all samples (with highest prevalence in African ancestry), was within the SLCA29 (GLUT9) gene; the GLUT9 uric transporter is a direct target of p53 and is implicated in antioxidant functions (56). Also, the 5q14.1 LTR lies within the RASGFR gene associated with regulation of dopamine neuron activity and reward sensitivity in alcohol use (57).…”

The Possible Effect of Vitamin D on Uric Acid Levels in Diabetic Patients

“…These findings may imply that treatment of Vitamin D deficiency in diabetic patients may help the regulation of diabetes and obesity and reduction in uric acid levels and may may lessen cardiovascular events in diabetic patients. 21 There are conflicting reports about its protective effect on carcinogenesis. [21][22][23] However, it is obvious that UA takes part in various metabolic, homeostatic and hemodynamic processes such as insulin resistance, obesity, dyslipidemia and metabolic syndrome(MS) HTA, for CVD.…”

“…21 There are conflicting reports about its protective effect on carcinogenesis. [21][22][23] However, it is obvious that UA takes part in various metabolic, homeostatic and hemodynamic processes such as insulin resistance, obesity, dyslipidemia and metabolic syndrome(MS) HTA, for CVD. [24][25][26][27][28] cerebrovascular disease, preeclampsia, and kidney disease.…”

GHK-Cu may Prevent Oxidative Stress in Skin by Regulating Copper and Modifying Expression of Numerous Antioxidant Genes

“…During oxidative stress, SLC2A9 undergoes p53-dependent induction, and functions as an antioxidant by suppressing ROS, DNA damage, and cell death [58]. NFE2L2 56 Nuclear respiratory factor 2 helps activate antioxidant responsive element-regulated genes which contribute to the regulation of the cellular antioxidant defense systems [59].…”