SLC35C2 promotes stemness and progression in hepatocellular carcinoma by activating lipogenesis

Metabolic reprogramming plays a critical role in tumorigenesis and progression, including hepatocellular carcinoma (HCC). The Solute Carriers (SLCs) family is responsible for the transport of a range of nutrients and has been linked to various cancers. Cancer stem cells (CSC) are a contributing factor to the recurrence and metastasis of HCC. However, the regulatory genes that govern this process remain unclear. The present study identified SLC35C2 as a crucial factor in maintaining the stem-cell characteristics of HCC cells through CRISPR-dCas9 screening. Further investigation demonstrated that SLC35C2 was significantly elevated in HCC tissues and correlated with a poor prognosis in HCC patients. It is an independent prognostic factor for HCC patients. The knockdown and overexpression of SLC35C2 inhibited or promoted stemness in HCC cell. Both in vitro and in vivo studies demonstrated that SLC35C2 promoted the proliferation, migration, invasion and metastasis in HCC cells. Through RNA-seq and lipidomics analysis, it was found that SLC35C2 regulated lipid reprogramming, particularly triglyceride synthesis. Mechanistically, SLC35C2 stimulated lipogenesis through the up-regulation of SREBP1, ACC, FAS, and SCD-1, thereby increasing lipid accumulation in HCC cells. SLC35C2 interacted with ACSL4, which plays a critical role in lipogenesis, and to protect it from degradation. Inhibition of ACSL4 with PRGL493 can reverse the lipogenesis, stemness and proliferation induced by SLC35C2 overexpression. In conclusion, our study demonstrates the pivotal role of SLC35C2 in stemness and malignant progression in HCC by promoting lipogenesis. These findings suggest that SLC35C2 is a prognostic marker and promising therapeutic target for HCC treatment.