Abstract
The decrease of ASPP1 (Apoptosis-Stimulating Protein of p53 1), a known p53 activator, has been linked to carcinogenesis and the cytotoxic resistance in various cancers, yet the underlying mechanisms of ASPP1 expression and its complex functions are not yet clear. Here, we report that ASPP1 forms an inter-regulatory loop with Early Growth Response 1 (EGR-1), and promotes apoptosis via inhibiting cyto-protective autophagy, independent of the well-documented p53-dependent mechanisms. We show that ASPP1 mRNA and protein were remarkably elevated by ectopic EGR-1 expression or endogenous EGR-1 activation, in cells with different tissue origins and p53 status. Conversely, RNAi-mediated EGR-1 knockdown suppressed ASPP1. The further mechanism studies revealed that ASPP1 promoter, mapped to −283/+88, which contained three conserved EGR-1 binding sites, was required for both binding and transactivity of EGR-1. In addition, we demonstrate that ASPP1 promoted EGR-1 in a positive feedback loop by preventing proteasome-mediated EGR-1 degradation or promoting EGR-1 nuclear import in response to anticancer natural compound Quercetin. Furthermore, albeit activating p53 in the nucleus is the well-studied function of ASPP1, we found that ASPP1 was predominately localized in the cytoplasm. Interestingly, the cytoplasmic ASPP1 retained its pro-apoptosis capability. Mechanistically, ASPP1 suppressed Atg5–Atg12 and also bound with Atg5–Atg12 to prevent its further complex formation with Atg16, resulting in the inhibition of cyto-protective autophagy. In conclusion, our results provide new insights into EGR-1/ASPP1 regulatory loop in sensitizing Quercetin-induced apoptosis. EGR-1/ASPP1, therefore, may be potentially used as therapeutic targets to improve cancer’s response to pro-apoptosis treatments.
Highlights
Apoptosis-Stimulating Protein of p53 1 (ASPP1), together with ASPP2 and iASPP, constitutes ASPP family
To determine whether EGR-1 regulates ASPP1 expression, ASPP1 was examined after forced expression of EGR-1 in HCT116 cells
EGR-1 mRNA and protein were significantly elevated at 8 h and peaked at 12 h post-transfection (Figures 1a and b)
Summary
Apoptosis-Stimulating Protein of p53 1 (ASPP1), together with ASPP2 and iASPP (inhibitor of ASPP), constitutes ASPP family. EGR-1/ASPP1 inter-regulatory loop promotes apoptosis K Zhao et al is a zinc-figure nuclear transcription factor and can be rapidly and transiently induced by various stimuli, such as H2O2, ionizing radiation, ultraviolet light (UV), hypoxia, serum and growth factors.[17,18] On activation, it binds to the GC-rich consensus sequences on gene promoters and regulates the downstream target transcription, leading to various biological effects, such as apoptosis, proliferation, angiogenesis, migration and differentiation, in a cellular context and stimulusdependent manner.[19,20] For instance, elevated EGR-1 promotes cell proliferation and may contribute to the occurrence of prostate cancers.[18] On the contrary, numbers of other studies have suggested that EGR-1 is a tumor suppressor. No doubts, dissecting the downstream targets will facilitate the understanding of complex network of EGR-1 signaling
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