Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Cancer cells showing low apoptotic effects following oxidative stress‐induced <jats:styled-content style="fixed-case">DNA</jats:styled-content> damage are mainly affected by growth arrest. Thus, recent studies focus on improving anti‐cancer therapies by increasing apoptosis sensitivity. We aimed at identifying a universal molecule as potential target to enhance oxidative stress‐based anti‐cancer therapy through a switch from cell cycle arrest to apoptosis. A <jats:styled-content style="fixed-case">cDNA</jats:styled-content> microarray was performed with hydrogen peroxide‐treated oesophageal squamous epithelial cancer cells <jats:styled-content style="fixed-case">TE</jats:styled-content>7. This cell line showed checkpoint activation <jats:italic>via</jats:italic> p21<jats:sup>WAF1</jats:sup>, but low apoptotic response following <jats:styled-content style="fixed-case">DNA</jats:styled-content> damage. The potential target molecule was chosen depended on the following demands: it should regulate <jats:styled-content style="fixed-case">DNA</jats:styled-content> damage response, cell cycle and apoptosis. As the transcription factor <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 is implicated in all these processes, we focused on this protein. We investigated checkpoint activation <jats:italic>via </jats:italic><jats:styled-content style="fixed-case">ATF</jats:styled-content>2. Indeed, <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 knockdown revealed <jats:styled-content style="fixed-case">ATF</jats:styled-content>2‐triggered p21<jats:sup>WAF1</jats:sup> protein expression, suggesting p21<jats:sup>WAF1</jats:sup> transactivation through <jats:styled-content style="fixed-case">ATF</jats:styled-content>2. Using chromatin immunoprecipitation (<jats:styled-content style="fixed-case">ChIP</jats:styled-content>), we identified a hitherto unknown <jats:styled-content style="fixed-case">ATF</jats:styled-content>2‐binding sequence in the p21<jats:sup>WAF1</jats:sup> promoter. p‐<jats:styled-content style="fixed-case">ATF</jats:styled-content>2 was found to interact with p‐c‐Jun, creating the <jats:styled-content style="fixed-case">AP</jats:styled-content>‐1 complex. Moreover, <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 knockdown led to c‐Jun downregulation. This suggests <jats:styled-content style="fixed-case">ATF</jats:styled-content>2‐driven induction of c‐Jun expression, thereby enhancing <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 transcriptional activity <jats:italic>via</jats:italic> c‐Jun‐<jats:styled-content style="fixed-case">ATF</jats:styled-content>2 heterodimerization. Notably, downregulation of <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 caused a switch from cell cycle arrest to reinforced apoptosis, presumably <jats:italic>via</jats:italic> p21<jats:sup>WAF1</jats:sup> downregulation, confirming the importance of <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 in the establishment of cell cycle arrest. 1‐Chloro‐2,4‐dinitrobenzene also led to <jats:styled-content style="fixed-case">ATF</jats:styled-content>2‐dependent G2/M arrest, suggesting that this is a general feature induced by oxidative stress. As <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 knockdown also increased apoptosis, we propose <jats:styled-content style="fixed-case">ATF</jats:styled-content>2 as a target for combined oxidative stress‐based anti‐cancer therapies.</jats:p>