HADHA promotes esophageal cancer progression by activating mTOR signaling and the SP1/MDM2 axis

Abstract

Esophageal cancer (EC) is one of the most recalcitrant cancers, with a 5-year survival rate of < 30%. The hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) plays an essential role in long-chain fatty acid metabolism, and dysregulation of HADHA has been demonstrated to be involved in a series of metabolic diseases and cancers. However, its role in cancers remains controversial. HADHA has seldom been investigated in EC, and little is known about how HADHA regulates the malignant progression of EC. In this study, we find that HADHA is significantly upregulated in EC tissues and is correlated with poor survival. HADHA knockdown markedly inhibits EC cell proliferation both in vitro and in vivo. The loss of HADHA also induces EC cell apoptosis, causes cell cycle arrest and inhibits cell migration. Additionally, RNA profiling reveals that mTOR signaling is significantly suppressed after HADHA knockdown. Mechanistically, HADHA interacts with SP1 and induces MDM2 expression. In conclusion, both mTOR signaling and the SP1-MDM2 axis participate in the HADHA-induced malignant behavior of EC cells.

1. Introduction

Esophageal cancer (EC) is one of the most lethal cancers, with a 5-year relative survival rate of only 20%–30% [1]. Even if it is detected in the early stages, the 5-year relative survival rate is still less than 50%, and this rate decreases to only 5% in the metastatic stage [2]. Globally, it is estimated that EC is the ninth most common cause of newly diagnosed tumors and ranks sixth in mortality. Additionally, the incidence of EC differs among geographic distributions, with Eastern Asians having the highest incidence in both men and women, partly because of the heavy burden in China [3]. Surgery remains the main strategy for the treatment of early-stage EC [4]. For localized and regional EC, trimodality (chemoradiation followed by surgery) has emerged as the standard treatment strategy, whereas advanced EC largely relies on traditional chemotherapy with immunotherapy (anti-PD-L1 agents) [5]. Current therapeutic advancements are limited, and new targets need to be further investigated.

The hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) is one of the two subunits of the mitochondrial trifunctional protein, which is responsible for the last three steps of the mitochondrial beta-oxidation of long-chain fatty acids [6]. Loss of HADHA expression results in the accumulation of long-chain fatty acid metabolites [7]. Accordingly, HADHA is essential for regulating energy metabolism and maintaining metabolic homeostasis, and HADHA dysfunction is involved in the pathogenesis of multiple human diseases, including metabolic disorders, cardiovascular diseases, and inflammatory bowel disease [8–10]. Recently, HADHA was reported to play an important role in tumorigenesis. In lung cancer and lymphoma, HADHA acts as an oncogene by promoting tumor cell proliferation and decreasing susceptibility to chemotherapy reagents [11,12]. In contrast, HADHA overexpression retards tumor growth in clear cell renal cell carcinoma and is correlated with favorable patient survival [13]. However, the role of HADHA in EC has rarely been discussed, and investigating its functional status could identify potential therapeutic targets for EC treatment.