The LncRNA FEZF1-AS1 promotes tumor proliferation in colon cancer by regulating the mitochondrial protein PCK2.

ABSTRACT

LncRNAs and metabolism represents two factors involved in cancer initiation and progression. However, the interaction between lncRNAs and metabolism remains to be fully explored. In this study, lncRNA FEZF1-AS1 (FEZF1-AS1) was found upregulated in colon cancer after screening all the lncRNAs of colon cancer tissues deposited in TCGA, the result of which was further confirmed by RNAscope staining on a colon tissue chip. The results obtained using FEZF1-AS1 knockout colon cancer cells (SW480 KO and HCT-116 KO) constructed using CRISPR/Cas9 system confirmed the proliferation, invasion, and migration-promoting function of FEZF1-AS1 in vitro. Mechanistically, FEZF1-AS1 associated with the mitochondrial protein phosphoenolpyruvate carboxykinase (PCK2), which plays an essential role in regulating energy metabolism in the mitochondria. Knockdown of FEZF1-AS1 greatly decreased PCK2 protein levels, broke the homeostasis of energy metabolism in the mitochondria, and inhibited proliferation, invasion, and migration of SW480 and HCT-116 cells. PCK2 overexpression in FEZF1-AS1 knockout cells partially rescued the tumor inhibitory effect on colon cancer cells both in vitro and in vivo. Moreover, PCK2 overexpression specifically rescued the abnormal accumulation of Flavin mononucleotide (FMN) and succinate, both of which play an important role in oxidative phosphorylation (OXPHOS). Overall, these results indicate that FEZF1-AS1 is an oncogene through regulating energy metabolism of the cell. This research reveals a new mechanism for lncRNAs to regulate colon cancer and provides a potential target for colon cancer diagnosis and treatment.