LETM1 Knockdown Promotes Autophagy and Apoptosis Through AMP-Activated Protein Kinase Phosphorylation-Mediated Beclin-1/Bcl-2 Complex Dissociation in Hepatocellular Carcinoma.

Baoyong Zhou,Zhongjun Wu,Xufu Wei,Xiong Yan,Heng Xiao,Changhong Yang,Ning Jiang,Zhengrong Shi

doi:10.3389/fonc.2020.606790

Abstract

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an inner mitochondrial membrane protein that has been reported to be involved in many primary tumors and may regulate many biological processes. However, the biological role and molecular mechanism of LETM1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that LETM1 was highly expressed in HCC tissues and cell lines and that higher LETM1 expression was associated with a lower overall survival rate in HCC patients. In addition, knockdown of LETM1 inhibited proliferation and enhanced apoptosis and autophagy in the Huh 7 and QGY-7701 liver cancer cell lines. Mechanistically, knockdown of LETM1 dissociated the Beclin-1/Bcl-2 complex through phosphorylation of AMPK and Bcl-2. These results demonstrated that LETM1 is involved in the development of HCC and could be a novel therapeutic target in HCC.

Highlights

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is prevalent in China, where approximately half of new cases and deaths occur [1, 2]
The messenger RNA levels of Leucine zipper/EF hand-containing transmembrane-1 (LETM1) in hepatocellular carcinoma (HCC) tissues and normal liver tissues from the Oncomine database are shown in Figure 1A, and Kaplan-Meier survival analysis indicated that upregulated LETM1 expression predicted poor prognosis (Figure 1B) (p < 0.05)
The data revealed that the expression of LETM1 in HCC tissues was higher than that in the corresponding adjacent tissues and that LETM1 was mainly localized in the cytoplasm, as shown in Figures 1F, G

Summary

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide and is prevalent in China, where approximately half of new cases and deaths occur [1, 2]. Due to the high invasiveness and high mortality rate of HCC, the survival time of most patients with advanced HCC is only approximately 2–3 months [3]. Autophagy can regulate cellular processes such as proliferation and apoptosis in liver cells [7]. A study suggested that disruption of the Beclin1/Bcl-2 complex is an effective mechanism for increasing mammalian autophagy, preventing premature aging [12]. Both Bcl-2 and Bcl-2L1 directly bind to Beclin-1 through their BH3 domains [13]. We speculated that AMPK may regulate autophagy and apoptosis through the Beclin-1/Bcl-2 complex

Methods

Results

Conclusion