The Role Of ASPP2 In Autophagy In Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common cancer worldwide. The mortality rate of HCC in China accounts for second of the death cause of malignant tumor. Recently, a growing amount of evidence show that autophagy is closely related with the development, relapse and chemoresistence of HCC recurrene. Therefore, it is important to understand the mechanisms underlying the involvement of autophagy in HCC. It may lead to novel preventive and therapeutic approaches for HCC.ASPP2 is an important member in ASPP2 (apoptosis stimulating proteins of p53) family of proteins, which regulate apoptosis through interaction with p53 and its family members. In the previous studies, our group has demonstrated that silence of ASPP2 expression promotes tumor growth and metasis in HCC. But the role of ASPP2 in autophagy in liver cancer is unclear. Here we investigate the role of ASPP2 in the regulation of autophagy in HCC.First, we found that downregulation of ASPP2 increases the numbers of autophagosome in HCC cells under nutritional stress. The conversion from LC3I to LC3II and the degradation of p62 were also increased after silencing of ASPP2 in HCC. However, the changes decreased with autophagic inhibitor treatment. It indicated that downregulation of ASPP2 could promote the progress of autophagy. Conversely, overexpression of ASPP2 could inhibit the autophagy in HCC.Then, we found the mechanism of ASPP2 regulating autophagy is through regulating Beclinl, which is a key autophagic gene. There are two parts. One is that ASPP2 could suppress the transcription of Beclin 1. ASPP2 could bind RelA/p65 and IκBα, inhibiting the phosphorlation of IκBα. Thus ASPP2 blocked RelA/p65entering into nucleus, which is an important step of RelA/p65 regulating transcription of its target genes, such as Beclin 1.Another mechanism is that ASPP2 could bind Beclin 1 directly. The interaction between ASPP2 and Beclin 1 inhibited formation of PI3KCIII-Beclin 1 complex and UVRAG binding Beclin 1. Thus, ASPP2 impaired the activation of PI3KCIII enzyme, suppressing the formation of autophagosome.Meanwhile, we fould silencing of ASPP2 could inhibit apoptosis through suppressing the progress of auotphagy, facilitating the survival of HCC cells under nutrient deprivation and chemotherapeutic treatment.This study reveals the role and the mechanisms of ASPP2 in regulating the progress of autophagy in HCC cells. These findings provide new insight into the molecular mechanisms of autophagy in HCC and may have potent therapeutic applications.