title: DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells.
abstract: 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 identified 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 (amino acids 1-26) of DDIT3. Importantly, knockdown of KAT2A down-regulated TNFRSF10A and TNFRSF10B and dramatically decreased promoter activity of cells transfected with luciferase reporter plasmid containing the AP-1 binding site (-304/-298) of the TNFRSF10A promoter, as well as cells transfected with luciferase reporter plasmid containing DDIT3 binding site (-276/-264) of the TNFRSF10B promoter. ChIP results suggest that KAT2A may participate in a KAT2A·DDIT3·phospho-JUN complex, or may participate in a KAT2A·DDIT3 complex and acetylate H3K9/K14, respectively. Moreover, we verified that TNFRSF10A mediates apoptosis triggered by endoplasmic reticulum stress in human lung cancer cells. Collectively, we demonstrate that DDIT3 and KAT2A cooperatively up-regulate TNFRSF10A and TNFRSF10B. Our findings highlight novel mechanisms underlying endoplasmic reticulum stress-induced TNFRSF10A and TNFRSF10B expressions and apoptosis. These findings will be helpful for elucidating mechanisms related to anticancer drugs in mediating apoptosis.
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China.
authors.forename: Tianliang
authors.initials: T
authors.lastname: Li
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Su
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China.
authors.forename: Yuanjiu
authors.initials: Y
authors.lastname: Lei
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China.
authors.forename: Xianfang
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Shandong University School of Life Sciences, Jinan 250100, China xgliu@sdu.edu.cn.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Liu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; C497249:DDIT3 protein, human; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C501179:KAT2A protein, human; D000099224:p300-CBP-Associated Factor
keywords: Apoptosis; DIT3; Endoplasmic Reticulum Stress (ER Stress); Histone Acetylase; KAT2A; Lung Cancer; TNFRSF10A; TNFRSF10B; Transcription Factor