BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY

Abstract

The dysregulation of branched‐chain amino acid (BCAA) metabolism and related enzymes has been greatly implicated in the progression of multiple types of cancer, whereas remains far from understood in melanoma. Here, we explored the role of the BCAA metabolism enzyme BCKDHA in melanoma pathogenesis and elucidated the underlying mechanisms. In vitro cell biology experiments and in vivo pre‐clinical mice model experiments were performed to investigate the role of BCKDHA in melanoma progression. RNA sequencing, immunohistochemical/immunofluorescence staining and bioinformatics analysis were used to examine the underlying mechanism. BCKDHA expression was prominently increased in both melanoma tissues and cell lines. The up‐regulation of BCKDHA promoted long‐term tumour cell proliferation, invasion and migration in vitro and tumour growth in vivo. Through RNA‐sequencing technology, it was found that BCKDHA regulated the expressions of lipogenic fatty acid synthase (FASN) and ATP‐citrate lyase (ACLY), which was thereafter proved to mediate the oncogenic role of BCKDHA in melanoma. Our results demonstrate that BCKDHA promotes melanoma progression by regulating FASN and ACLY expressions. Targeting BCKDHA could be exploited as a promising strategy to restrain tumour progression in melanoma.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer

“…Recently, the enzyme BCKDHA, known as branched-chain keto acid dehydrogenase E1 subunit alpha, which is involved in branched-chain amino acid metabolism, has been found to regulate the expression of FASN and ATP-citrate lyase (ACLY) in melanoma. This regulation enhances proliferation, invasion, migration, and tumor growth in vivo [ 58 ]. The expression of branched-chain amino acid transaminase 2 (BCAT2) also affects the levels of FASN and ACLY, promoting De Novo lipogenesis and facilitating melanoma progression.…”

“…The expression of branched-chain amino acid transaminase 2 (BCAT2) also affects the levels of FASN and ACLY, promoting De Novo lipogenesis and facilitating melanoma progression. This progression is driven by the epigenetic modification of both FASN and ACLY via p300-dependent histone acetylation [ 58 ]. Based on these reports, FASN is widely recognized as a promising therapeutic target for melanoma and cutaneous squamous cell carcinoma.…”