As a novel p53 direct target, bidirectional gene HspB2/αB-crystallin regulates the ROS level and Warburg effect

Many mammalian genes are composed of bidirectional gene pairs with the two genes separated by less than 1.0 kb. The transcriptional regulation and function of these bidirectional genes remain largely unclear. Here, we report that bidirectional gene pair HspB2/αB-crystallin, both of which are members of the small heat shock protein gene family, is a novel direct target gene of p53. Two potential binding sites of p53 are present in the intergenic region of HspB2/αB-crystallin. p53 up-regulated the bidirectional promoter activities of HspB2/αB-crystallin. Actinomycin D (ActD), an activator of p53, induces the promoter and protein activities of HspB2/αB-crystallin. p53 binds to two p53 binding sites in the intergenic region of HspB2/αB-crystallin in vitro and in vivo. Moreover, the products of bidirectional gene pair HspB2/αB-crystallin regulate glucose metabolism, intracellular reactive oxygen species (ROS) level and the Warburg effect by affecting metabolic genes, including the synthesis of cytochrome c oxidase 2 (SCO2), hexokinase II (HK2), and TP53-induced glycolysis and apoptosis regulator (TIGAR). The ROS level and the Warburg effect are affected after the depletion of p53, HspB2 and αB-crystallin respectively. Finally, we show that both HspB2 and αB-crystallin are linked with human renal carcinogenesis. These findings provide novel insights into the role of p53 as a regulator of bidirectional gene pair HspB2/αB-crystallin-mediated ROS and the Warburg effect.