Reactive oxygen species increase HEPN1 expression via activation of the XBP1 transcription factor

• We discovered a new ROS-upregulated gene, HEPN1.
• ROS-induced XBP1s binds to HEPN1 promoter and acts as a transcriptional activator.
• HEPN1 increases p53, p21, and Bax in HepG2 cells carrying wild type p53.

Hepatocellular carcinoma downregulated 1 (HEPN1), a cell growth arrest- and apoptosis-related gene, is suppressed in hepatocellular carcinoma (HCC). However, transcriptional control of HEPN1 has not been characterized. Here, we show that exposure to reactive oxygen species (ROS) leads to upregulation of the mRNA expression of HEPN1 in HCC cell lines. Mechanistically, ROS increase production of an alternately spliced form of X-box binding protein 1 (XBP1s) and XBP1s increases HEPN1 expression by binding to the HEPN1 promoter, thereby acting as a transcriptional activator. Finally, HEPN1 overexpression increases the expression of p53, p21, and Bax, all of which are ROS-upregulated proteins.