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

TL;DR

This study shows how the KRASG12D mutation promotes pancreatic cancer by suppressing SIRT3 through RCC1, offering a new therapeutic target.

Contribution

The study identifies a novel mechanism involving SIRT3 and RCC1 in KRASG12D-driven pancreatic tumorigenesis.

Findings

KRASG12D significantly down-regulates SIRT3, an NAD-dependent deacetylase.

Forced SIRT3 overexpression inhibits pancreatic cancer cell proliferation in vitro and in vivo.

RCC1 mediates KRASG12D's suppression of SIRT3, and its knockdown restores SIRT3 and reduces tumor formation.

Abstract

KRASG12D 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 KRASG12D-driven malignant transformation, we measured the transcriptomic alterations at various time points after induction of KRASG12D 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 KRASG12D. 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 KRASG12D 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.

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