SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis

Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived alpha-ketoglutarate (alpha-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS- mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested alpha-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of alpha-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.

Automated summary

Emerging evidence shows that targeting glutamine metabolism may be a promising therapeutic strategy for KRAS-mutant colorectal cancer (CRC). In this study, researchers discovered that solute carrier 25 member 21 (SLC25A21) depletion accelerated the growth and metastasis of KRAS-mutant CRC cells by inhibiting Gln-derived alpha-ketoglutarate (alpha-KG) efflux from mitochondria, leading to increased GTP availability for persistent KRAS activation. Restoring SLC25A21 expression impaired cetuximab resistance in KRAS-mutant CRC.