Transcriptional Regulation of De Novo Lipogenesis by SIX1 in Liver Cancer Cells

Abstract De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (SIX1) is shown to directly increase the expression of DNL‐related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl‐CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 （HBO1/KAT7）, thus promoting lipogenesis. SIX1 expression is regulated by insulin/lncRNA DGUOK‐AS1/microRNA‐145‐5p axis, which also modulates DNL‐related gene expression as well as DNL. The DGUOK‐AS1/microRNA‐145‐5p/SIX1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, SIX1 expression is positively correlated with DGUOK‐AS1 and SCD1 expression and is negatively correlated with microRNA‐145‐5p expression. DGUOK‐AS1 is a good predictor of prognosis. Thus, the DGUOK‐AS1/microRNA‐145‐5p/SIX1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.