Biological Role and Mechanism of Lipid Metabolism Reprogramming Related Gene ECHS1 in Cancer

Abstract

Cancer is a major threat to human health today. Although the existing anticancer treatments have effectively improved the prognosis of some patients, there are still other patients who cannot benefit from these well-established strategies. Reprogramming of lipid metabolism is one of the typical features of cancers. Recent studies have revealed that key enzymes involved in lipid metabolism may be effective anticancer therapeutic targets, but the development of therapeutic lipid metabolism targets is still insufficient. ECHS1 (enoyl-CoA hydratase, short chain 1) is a key enzyme mediating the hydration process of mitochondrial fatty acid β-oxidation and has been observed to be abnormally expressed in a variety of cancers. Therefore, with ECHS1 and cancer as the main keywords, we searched the relevant studies of ECHS1 in the field of cancer in Pubmed, summarized the research status and functions of ECHS1 in different cancer contexts, and explored its potential regulatory mechanisms, with a view to finding new therapeutic targets for anti-metabolic therapy. By reviewing and summarizing the retrieved literatures, we found that ECHS1 regulates malignant biological behaviors such as cell proliferation, metastasis, apoptosis, autophagy, and drug resistance by remodeling lipid metabolism and regulating intercellular oncogenic signaling pathways. Not only that, ECHS1 exhibits early diagnostic and prognostic value in clear cell renal cell carcinoma, and small-molecule inhibitors that regulate ECHS1 also show therapeutic significance in preclinical studies. Taken together, we propose that ECHS1 has the potential to serve as a therapeutic target of lipid metabolism.

The p53 tumor suppressor regulates AKR1B1 expression, a metastasis-promoting gene in breast cancer

“…For example, Echs1 was upregulated upon AKR1B1 overexpression. This enzyme catalyzes the hydration of short-chain enoyl-CoAs, as part of the process of fatty acid β-oxidation in mitochondria ( Hu et al, 2022 ). Among downregulated proteins, we found Cbr4, a mitochondrial carbonyl reductase involved in mitochondrial fatty acid synthesis (FAS) ( Venkatesan et al, 2014 ).…”

“…We also observed an alteration of mitochondrial enzymes related to fatty acid metabolism that suggests an enhancement of fatty acid β-oxidation. The alteration of lipid metabolism in cancer cells often includes enhanced fatty acid β-oxidation as a source of NADH, FADH 2 , and NADPH ( Hu et al, 2022 ), while relying in cytosolic FAS for lipid generation ( Röhrig and Schulze, 2016 ). In this context, Cbr4 downregulation may reduce acetyl-CoA consumption for mitochondrial FAS, favoring its bioavailability for other reactions.…”

Expression and clinical significance of ECHS1 in gastric cancer

“…ECHS1 is a critical FAO enzyme essentially involved in fatty acid metabolic reprogramming 25 . Additionally, ECHS1 is linked with the development of different tumors and induces cancer malignancy by lipid metabolism remodeling and intercellular oncogenic signaling pathways modulation.…”

PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis

“…Cancer lipid metabolic reprogramming is implicated in the biosynthesis of fatty acids, ceramides, and sphingolipids, which regulates various signaling pathways important for cancer cells. Therefore, cancer cells have increased de novo synthesis and β-oxidation of FFAs [219]. Through HIF-dependent modulation of proteins involved in fatty acids metabolism (uptake, synthesis, usage, storage), in hypoxic conditions, lipogenesis is enhanced.…”

“…Młynarczyk G and his research team detected in ccRCC tissues accumulation of sphingosine, sphingosine-1-phosphate (S1P), ceramide, dihydrosphingosine, and dihydroceramide compared with healthy subjects [222]. In ccRCC, lipid accumulation will affect cellular energy homeostasis and lipid signal transduction [219], contributing to cancer cell proliferation, progression, and metastasis [223,224].…”