Dataset Information

NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis

ABSTRACT: During metastasis, cancer cells face significant survival pressures, including treatment-induced ferroptosis. Adaptation to ferroptosis stress orchestrates the metastasis of colorectal cancer (CRC) cells. However, the reciprocal regulatory mechanisms of ferroptosis and metastasis remain unknown. Here, through a CRISPR–Cas9 screen, we discovered that N-acetylneuraminate synthase (NANS) is a positive regulator of ferroptosis in CRC, regardless of its metabolic function. Moreover, NANS expression is downregulated and is clinically associated with poor prognosis in CRC patients. In a ferroptotic stress environment, NANS is phosphorylated by cyclin-dependent kinase 1 (CDK1) at serine 275 (S275), and phosphorylated NANS (NANS pS275) dissociates from TAK1 and is subsequently ubiquitinated by the E3 ligase ubiquitin-conjugating enzyme E2 N (UBE2N) at lysine 246 (K246) for degradation, which further activates TAK1 and nuclear factor κB (NF-κB) signaling and the expression of the ferroptosis negative regulatory factor FTH1, resulting in ferroptosis resistance and finally promoting metastasis. Furthermore, the NANS pS275 intensity is correlated with the degree of malignancy and the prognosis of CRC patients. Our study revealed that NANS inhibits CRC metastasis by promoting ferroptosis and that the CDK1-mediated phosphorylation of NANS at S275 may guide the utilization of chemical compounds to promote ferroptosis and thus block CRC metastasis.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Ziyang Wang

LAB HEAD: Ziyang Wang

PROVIDER: PXD062501 | Pride | 2025-05-08

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 5

Similar Datasets

Project description:Background Colorectal cancer (CRC), a malignancy with high incidence and mortality rates, presents particularly severe prognoses at the stages of invasion and metastasis despite significant advancements in diagnostic and therapeutic technologies. The tumour microenvironment, especially the extracellular matrix (ECM) stiffness, has garnered considerable attention for its impact on CRC progression and metastasis. However, the precise relationship and molecular mechanisms between ECM stiffness and CRC prognosis remain unclear. Methods This study included 107 CRC patients. Tumor stiffness was assessed using magnetic resonance elastography (MRE), and collagen content was analysed with Masson staining. CRC cell lines SW480 and HCT116 were cultured on matrices of varying stiffness, followed by transcriptome sequencing to identify stiffness-related differential genes and investigate their functions and signalling pathways. Additionally, an HSF4 knockout CRC cell model was constructed to evaluate the effects of HSF4 on cell proliferation, migration, and invasion through both in vitro and in vivo experiments, exploring its role in tumour growth and metastasis. Results The study found that CRC tumour stiffness was significantly higher than normal tissue and positively correlated with collagen content and TNM staging. Transcriptome analysis revealed that high-stiffness matrices significantly regulated cell functions and signalling pathways. High expression of HSF4 was strongly associated with tumour stiffness and poor prognosis. HSF4 expression increased with higher TNM stages in CRC tissues, and its knockout significantly inhibited cell proliferation, migration, and invasion, particularly on high-stiffness matrices. In vivo experiments further confirmed that HSF4 promoted tumour growth and metastasis, independent of collagen protein increase. Conclusion This study reveals a close relationship between tumour stiffness and CRC prognosis, identifying HSF4 as a critical player in CRC progression. HSF4 promotes tumour proliferation and metastasis by regulating EMT-related signalling pathways, with its high expression closely linked to tumour stiffness. Although LOXL1 increased collagen content and a-SMA expression, HSF4's role in promoting tumour growth and metastasis was independent of collagen protein. HSF4 holds potential as a target for CRC prognosis evaluation and treatment. Future research should further explore the regulatory mechanisms of HSF4 and its potential for clinical application.

			Action	DRS
	NANS1.raw	Raw
	NANS2.raw	Raw
	NANSRSL1.raw	Raw
	NANSRSL2.raw	Raw
	result.zip	Other

Dataset Information

NANS suppresses NF-κB signaling to promote ferroptosis by perturbing iron homeostasis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets