ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1

Jiawen Zhang,Qingying Wang,Yingze Wei,Qingxian Li,Jing Zhang

doi:10.1038/s41419-019-2050-y

Abstract

Enhanced glycolysis has been identified as a hallmark of cancer. As a novel oncogene, ACTL6A is aberrantly amplified in several types of human cancers and has been shown to regulate tumor growth and progression. However, the roles of ACTL6A in the development of ovarian cancer and the regulation of cancer glucose metabolism are mostly unknown. Here we show that ACTL6A is overexpressed in ovarian cancers compared with adjacent non-tumor tissues, and that ACTL6A overexpression correlates with poor prognosis. Silencing of ACTL6A in vitro inhibits proliferation, clonal growth, and migration, and decreases glucose utilization, lactate production, and pyruvate levels of ovarian cancer cells. We found a positive correlation between ACTL6A and PGK1 expression in ovarian cancer tissues. Enforced ACTL6A expression increased PGK1 expression, whereas knockdown of ACTL6A had the opposite effect. Altered ACTL6A expression inhibits the tumorigenicity of ovarian cancer cells in vivo by downregulating PGK1. In addition, the expression of ACTL6A is regulated by follicle-stimulating hormone (FSH) stimulation via PI3K/AKT pathway. Importantly, ACTL6A regulates FSH-enhanced glycolysis in ovarian cancer. Taken together, our findings highlight the critical role of ACTL6A in ovarian cancer development and identify its contribution to glucose metabolism of cancer cells.

Highlights

Epithelial ovarian cancer (EOC) is generally diagnosed at an advanced stage and is the most lethal gynecological cancer
The ACTL6A gene is frequently amplified in ovarian cancer Our analysis of genomic profiling of several cancer types in TCGA demonstrated that ACTL6A gene is amplified in
We identified the critical roles of ACTL6A and Phosphoglycerate kinase 1 (PGK1) expression in glycolysis in ovarian cancer and the novel function for ACTL6A in follicle-stimulating hormone (FSH)-induced glycolysis (Fig. 8)

Summary

Introduction

Epithelial ovarian cancer (EOC) is generally diagnosed at an advanced stage and is the most lethal gynecological cancer. In 2018, ~295,000 new EOC cases and 185,000 cancer deaths are projected to occur globally[1]. Despite various advances in early detection strategies and systematic therapies for EOC made over the past decades, about 75% of patients are diagnosed with advanced-stage disease and the 5-year survival rate still remains low[2]. The need to identify potential targets for therapeutic intervention to improve EOC patient outcomes is urgent. Mounting evidence indicates that cancer cells have enhanced glucose uptake and lactate accumulation to SWI/SNF complexes ( known as BAF complex) are evolutionarily conserved multi-subunit protein complexes that mediate chromatin-remodeling processes, which is crucial for the regulation of gene expression[13]. Official journal of the Cell Death Differentiation Association

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