KRASG12D mutation promotes pancreatic tumorigenesis by suppressing sirtuin three via the guanine nucleotide exchange factor RCC1

KRAS^G12D mutation is a prevalent gain-of-function mutation that drives pancreatic cancer tumorigenesis, but the underlying mechanisms that promote KRAS-induced cell proliferation and tumor formation remain elusive. To uncover the molecular pathways that facilitate KRAS^G12D-driven malignant transformation, we measured the transcriptomic alterations at various time points after induction of KRAS^G12D expression in human pancreatic normal epithelial cells. KEGG pathway enrichment of the differentially expressed genes (DEGs) showed that the major DEGs were located in pathways that regulate nicotinate/nicotinamide metabolism, TNF signaling, and microRNAs associated with cancer. Among these molecular alterations, the NAD-dependent deacetylase gene SIRT3 was significantly down-regulated by KRAS^G12D. Conversely, forced overexpression of SIRT3 inhibited pancreatic cancer cell proliferation both in vitro and in vivo. Mechanistic study identified RCC1 as a key molecule that mediated KRAS^G12D inhibition of SIRT3 transcription. Knockdown of RCC1 in pancreatic cancer cells restored SIRT3 expression and impaired tumor formation in vivo. Overall, our study has revealed a previously unrecognized mechanism by which oncogenic KRAS promotes tumor development through down-regulation of the SIRT3-mediated tumor suppression pathway, and has also identified RCC1 as a potential therapeutic target for treatment of cancer patients with KRAS mutations.