ER stress activates TAp73α to promote colon cancer cell apoptosis via the PERK-ATF4 pathway

Colorectal cancer (CRC) is the fourth most diagnosed cancer worldwide. 43% of CRCs harbor p53 mutations. The tumor suppressor p53 induces cell growth arrest and/or apoptosis in response to stress, including endoplasmic reticulum (ER) stress. It has been documented that the p53 gene is mutated in more than 50% of human tumors and loses its tumor suppressor function, suggesting that ER stress-induced apoptosis might not rely on p53. In this study, we found that activation of ER stress promotes p53 null colon cancer cell apoptosis concomitant with an increased level of the TAp73a protein, a homologue of p53 in vitro and in vivo. Knockdown of TAp73a partially restores ER stress-induced apoptosis, indicating that ER stress stimulates apoptosis in a manner dependent on TAp73a, but not p53. Furthermore, we found that ER stress activates TAp73a mRNA and protein expression through PERK signalling, a branch of the unfolded protein response (UPR). Moreover, PERK promotes TAp73a expression by upregulating the expression of the transcription factor ATF4. ATF4 directly activates the transcription of TAp73a. Consistent with this finding, ATF4 knockdown inhibited PERK-or ER stress-induced TAp73a expression. Our findings reveal that ER stress activates TAp73a to promote colon cancer cell apoptosis via the PERK-ATF4 signalling. Therefore, prolonged ER stress or upregulation of TAp73a might be a therapeutic strategy for colon cancer.