Melanoma is the most lethal
skin cancer originating from the malignant transformation of epidermal melanocyte. The dysregulation of cellular metabolism is a hallmark of
cancer, including in
melanoma. Aberrant
branched-chain amino acids (BCAA) metabolism and related
enzymes has been greatly implicated in the progression of multiple types of
cancer, whereas remains far from understood in
melanoma. Herein, we reported that the critical BCAA metabolism
enzyme branched-chain amino acid transaminase 2 (BCAT2) is an oncogenic factor in
melanoma by activating lipogenesis via the epigenetic regulation of
fatty acid synthase (FASN) and
ATP-citrate lyase (ACLY) expressions. Firstly, we found that BCAT2 expression was prominently increased in
melanoma, and highly associated with clinical stage. Then, it was proved that the deficiency of BCAT2 led to impaired
tumor cell proliferation, invasion and migration in vitro, and
tumor growth and
metastasis in vivo. Further,
RNA sequencing technology and a panel of biochemical assays demonstrated that BCAT2 regulated de novo lipogenesis via the regulation of the expressions of both FASN and ACLY. Mechanistically, the inhibition of BCAT2 suppressed the generation of intracellular
acetyl-CoA, mitigating P300-dependent
histone acetylation at the promoter of FASN and ACLY, and thereby their transcription. Ultimately,
zinc finger E-box binding homeobox 1 (ZEB1) was identified as the upstream transcriptional factor responsible for BCAT2 up-regulation in
melanoma. Our results demonstrate that BCAT2 promotes
melanoma progression by epigenetically regulating FASN and ACLY expressions via P300-dependent
histone acetylation. Targeting BCAT2 could be exploited as a promising strategy to restrain
tumor progression in
melanoma.