EP300 and neoplasm: Taken together, we disclose a novel p53/lnc‐Ip53 negative feedback loop, in which p53 is activated by various stresses, then binds to the lnc‐Ip53 promoter and transactivates lnc‐Ip53 expression, whereas lnc‐Ip53 directly interacts with HDAC1 to prevent its degradation and associates with p300 to attenuate its activity, leading to abrogation of p53 acetylation/activity, which consequently promotes tumor development and chemoresistance (Figure 8).