nNOS-mediated S-nitrosylation of TCOF1 regulates KRAS proteostasis to suppress hepatoblastoma progression
Meng Wang, Yupeng Wang, Yue Qian, Ziyan Luo, Siqi Dong, zhuoyan Li, Lingling Wu, Fang Yu, Zihua Lin, Lin Qiu, Hua Jiang, Linna Yu
TL;DR
This study shows that nNOS suppresses liver tumor growth by modifying a protein that reduces KRAS levels, a key driver of cancer.
Contribution
The study identifies a novel nNOS-TCOF1-KRAS regulatory axis and a potential NO-based therapy for KRAS-driven cancers.
Findings
nNOS downregulation correlates with increased hepatoblastoma malignancy in clinical samples.
nNOS overexpression inhibits tumor growth by reducing KRAS levels via TCOF1 S-nitrosylation.
The TCOF1-KRAS interaction is disrupted by nNOS, promoting KRAS degradation.
Abstract
Neuronal nitric oxide synthase (nNOS) plays dual roles in tumorigenesis, but its function in hepatoblastoma (HB) remains unclear. Analysis of 30 clinical HB samples reveals significant nNOS downregulation, correlating with tumor malignancy. Overexpression of nNOS inhibits HB cell proliferation and tumor growth in vitro and in vivo. Multi-omics analysis identifies the MAPK pathway as a key target, with KRAS protein levels most prominently reduced. Mechanistically, nNOS induces S-nitrosylation of TCOF1 at cysteine 644, disrupting TCOF1-KRAS interaction and thereby accelerating KRAS protein degradation. These findings establish the nNOS-TCOF1-KRAS axis as a critical regulator of HB progression and propose a novel NO-based therapeutic strategy for KRAS-driven cancers.
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Taxonomy
TopicsNitric Oxide and Endothelin Effects · Mitochondrial Function and Pathology · Cancer, Hypoxia, and Metabolism