DDIT3 and KAT2A regulate TNFRSF10A and TNFRSF10B expression in endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells [Signal Transduction]

March 13th, 2015 by Li, T., Su, L., Lei, Y., Liu, X., Zhang, Y.,

TNFRSF10A and TNFRSF10B are cell surface receptors that bind to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mediate the extrinsic pathway of apoptosis. However, the mechanisms of transcriptional regulation of TNFRSF10A and TNFRSF10B remain largely uncharacterized. In this study, two putative DDIT3 binding sites (-1636/-1625; -374/-364) and a putative AP-1 binding site (-304/-298) were identiļ¬ed in the TNFRSF10A promoter region. We found that DDIT3 interacts with phospho-JUN, and the DDIT3/phospho-JUN complex binds to the AP-1 binding site (-304/-298) within the TNFRSF10A promoter region. In addition, we confirmed that KAT2A physically interacts with the N-terminal region (aa 1-26) of DDIT3. Importantly, knockdown of KAT2A downregulated TNFRSF10A and TNFRSF10B and dramatically decreased promoter activity of cells transfected with luciferase reporter plasmid containing AP-1 binding site (-304/-298) of the TNFRSF10A promoter, and cells transfected with luciferase reporter plasmid containing DDIT3 binding site (-276/-264) of the TNFRSF10B promoter. Chromatin immunoprecipitation (ChIP) results suggest that KAT2A may participate in a KAT2A/DDIT3/phospho-JUN complex, or a KAT2A/DDIT3 complex and acetylate H3K9/K14, respectively. Moreover, we verified that TNFRSF10A mediates apoptosis triggered by ER stress in human lung cancer cells. Collectively, we demonstrate that DDIT3 and KAT2A cooperatively upregulate TNFRSF10A and TNFRSF10B. Our findings highlight two distinct mechanisms underlying ER stress-induced TNFRSF10A and TNFRSF10B expressions and apoptosis. These findings will be helpful for elucidating mechanisms related to anticancer drugs in mediating apoptosis.
  • Posted in Journal of Biological Chemistry, Publications
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