Related Experiment Video
Updated: May 12, 2025
Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
P4HB, a novel succinated protein, is essential for fumarate-induced cancer metastasis
Xinyi Song1, Haipeng Rao1, Chunchun Huang1
1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 Wen Yuan Road, Nanjing 210023, China.
Abstract:
Fumarate hydratase (FH) catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle. Its deficiency leads to fumarate accumulation, which is associated with kidney cancer metastasis, though the exact mechanisms remain unclear. Here, we identify prolyl 4-hydroxylase beta (P4HB) as a novel fumarate target in FH-deficient cancer cells that promotes migration and invasion. FH knockdown in human renal cancer cells significantly enhanced migratory and invasive capacities by 10- and 8-fold, respectively. Mechanistically, fumarate-induced succination stabilizes P4HB, promoting type I collagen production and enhancing tumor metastasis. P4HB knockdown markedly suppresses FH deficiency-induced metastasis in xenograft models. Fluorescence intensity in the FH knockdown group was about 10-fold higher, and tumor-bearing liver weight was approximately 1.5-fold greater than that in the FH and P4HB co-knockdown group. These results underscore the pivotal role of P4HB in metastasis. Additionally, we reveal NDP52 as a specific autophagy receptor that recognizes and binds to P4HB, mediating its degradation through the autophagy-lysosome pathway. However, succination of P4HB disrupts this recognition, interaction, and degradation, stabilizing P4HB. Together, these findings provide new insights into how fumarate-mediated succination affects P4HB protein stability and cancer metastasis, and suggest that P4HB could serve as a potential therapeutic target in FH-deficient cancers.
Insights
Fumarate hydratase (FH) deficiency causes fumarate buildup, promoting kidney cancer metastasis. We found prolyl 4-hydroxylase beta (P4HB) stabilization by fumarate drives this spread, offering a new therapeutic target.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Fumarate hydratase (FH) deficiency is linked to kidney cancer metastasis.
- The precise mechanisms driving FH deficiency-induced metastasis remain largely unknown.
- Fumarate accumulation is a key consequence of FH deficiency.
Purpose of the Study:
- To identify novel targets of fumarate in FH-deficient cancer cells.
- To elucidate the role of these targets in promoting cancer cell migration and invasion.
- To explore potential therapeutic strategies for FH-deficient cancers.
Main Methods:
- Utilized FH knockdown in human renal cancer cells to assess migratory and invasive capacities.
- Investigated the mechanism of fumarate-induced P4HB stabilization via succination.
- Employed xenograft models to evaluate the impact of P4HB knockdown on metastasis.
- Identified NDP52 as an autophagy receptor involved in P4HB degradation.
Main Results:
- FH knockdown significantly increased cancer cell migration (10-fold) and invasion (8-fold).
- Fumarate-induced succination stabilizes prolyl 4-hydroxylase beta (P4HB), enhancing type I collagen production and metastasis.
- P4HB knockdown suppressed FH deficiency-induced metastasis in vivo, with reduced fluorescence intensity and liver weight.
- NDP52-mediated degradation of P4HB is disrupted by P4HB succination, leading to protein stabilization.
Conclusions:
- Prolyl 4-hydroxylase beta (P4HB) is a critical mediator of metastasis in FH-deficient cancers.
- Fumarate-induced P4HB stabilization is a key mechanism driving cancer progression.
- Targeting P4HB presents a promising therapeutic strategy for FH-deficient renal cell carcinoma.
Related Concept Videos
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
02:23Abnormal Proliferation
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
02:38Mitogens and the Cell Cycle