Enoyl-coenzyme A hydratase in cancer

Highlights

• Potential role of Enoyl-coenzyme A hydratase in cancer

Abstract

Enoyl-CoA hydratase (Ech) catalyzes the second step in the physiologically important beta-oxidation pathway of fatty acid metabolism. The enzyme was reported to be associated with the progression, metastasis and drug resistance of cancers. It might function as a tumor promoter or a tumor suppressor for certain cancers depending on the particular type or stage of tumor cells/tissues. In this review, Ech's association with malignant tumors as well as its potential mechanisms is discussed and summarized. The enzyme might be useful in the diagnosis, treatment and prognosis determination of certain tumors.

Introduction

Fatty acid β-oxidation occurs in mitochondria and peroxisome. Most of the mitochondrial energy is generated via fatty-acid oxidation when the supply of glucose is limited [1]. The β-oxidation spiral of fatty acid degradation consists of four enzymatic transformations that reduce the acyl chain length by two carbons in each cycle, resulting in the formation of acetyl-CoA in each cycle [2], [3]. The four enzymes involved in this process are acyl-CoA dehydrogenase (AD), enoyl-CoA hydratase (Ech), (l)-3-hydroxyacyl-CoA dehydrogenase (HAD), and thiolase (Fig. 1). Ech is the second enzyme in this metabolic cycle [3] and catalyzes the stereospecific hydration of 2-enoyl-CoA into the corresponding S- or R-3-hydroxyacyl-CoA, where the S-specific and the R-specific are known as Ech-1 and Ech-2, respectively [4].

Cancer is associated with a variety of lipid metabolic alterations, and indeed, deregulation of Ech has been reported to play important roles in tumor occurrence, development, metastasis and drug resistances. Fatty acid synthase, the enzyme responsible for de novo fatty acid synthesis, has recently been proposed as a therapeutic drug target [5], and interestingly also, alpha-methylacyl-CoA racemase (AMACR) involved in the beta oxidation of branched-chain fatty acids and fatty acid derivatives, has been identified as a molecular marker for prostate cancer [6].

Accumulated evidence indicates that Ech might specifically function as a tumor promoter candidate in pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, prostate cancer and breast cancer; on the other hand, Ech might conversely function as a tumor suppresser gene in renal cell carcinoma, bladder cancer, endometrial cancer, B-cell chronic lymphoid leukemia and conjunctival melanoma. So far the role of Ech is uncertain in hepatocellular cancer and gastric cancer with regards to whether it is a tumor suppressor gene or an oncogene. In these two cancers, it shows paradoxical expression levels among subtypes of tissues, different stages of tumors, or between clinical tumor tissues and tumor cell lines. Despite Ech having been known for decades, its role in tumor progression is still unclear and requires more investigations. This review summarizes recent research process on Ech and its relevant mechanisms in cancers. The summarized associations of Ech with cancer are shown in Table 1.