KRASG12D Mutation Promotes Pancreatic Tumorigenesis by Suppressing Sirtuin Three via the Guanine Nucleotide Exchange Factor RCC1

Authors

Taoyi Mai
Mengwen Wang
Ya Qiu
Wenhua Lu
Hongyu Wu
Shuna Chen
Paul J Chiao
Peng Huang

Language

English

Publication Date

12-13-2025

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2025.111057

PMID

41391757

PMCID

PMC12804135

PubMedCentral® Posted Date

12-13-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

gene regulation, KRAS, pancreatic cancer, RCC1, SIRT3

Published Open-Access

yes

Recommended Citation

Mai, Taoyi; Wang, Mengwen; Qiu, Ya; et al., "KRASG12D Mutation Promotes Pancreatic Tumorigenesis by Suppressing Sirtuin Three via the Guanine Nucleotide Exchange Factor RCC1" (2025). Faculty, Staff and Student Publications. 5481.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5481