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SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression
Yu-Hang Zhang1, Wen-Na Shi2, Shu-Hua Wu3
1Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Abstract:
Aberrant sphingolipid metabolism has been implicated in chemoresistance, but the underlying mechanisms are still poorly understood. Herein we revealed a previously unrecognized mechanism of 5-fluorouracil (5-FU) resistance contributed by high SphK2-upregulated dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), which is evidenced from human CRC specimens, animal models, and cancer cell lines. TMA samples from randomly selected 60 CRC specimens firstly identified the clinical correlation between high SphK2 and increased DPD (p < 0.001). Then the regulatory mechanism was explored in CRC models of villin-SphK2 Tg mice, SphK2-/-mice, and human CRC cells xenografted nude mice. Assays of ChIP-Seq and luciferase reporter gene demonstrated that high SphK2 upregulated DPD through promoting the HDAC1-mediated H3K56ac, leading to the degradation of intracellular 5-FU into inactive α-fluoro-β-alanine (FBAL). Lastly, inhibition of SphK2 by SLR080811 exhibited excellent inhibition on DPD expression and potently reversed 5-FU resistance in colorectal tumors of villin-SphK2 Tg mice. Overall, this study manifests that SphK2high conferred 5-FU resistance through upregulating tumoral DPD, which highlights the strategies of blocking SphK2 to overcome 5-FU resistance in CRC.
Insights
High sphingosine kinase 2 (SphK2) increases dihydropyrimidine dehydrogenase (DPD) in colorectal cancer (CRC), causing resistance to 5-fluorouracil (5-FU). Blocking SphK2 may overcome this chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sphingolipid metabolism alterations are linked to chemotherapy resistance, but mechanisms remain unclear.
- 5-fluorouracil (5-FU) is a key chemotherapy agent for colorectal cancer (CRC).
- Dihydropyrimidine dehydrogenase (DPD) degrades 5-FU, impacting its efficacy.
Purpose of the Study:
- To elucidate the mechanism of 5-FU resistance mediated by sphingolipid metabolism in CRC.
- To investigate the role of Sphingosine Kinase 2 (SphK2) in regulating DPD expression and 5-FU resistance.
- To evaluate SphK2 inhibition as a strategy to overcome 5-FU resistance in CRC.
Main Methods:
- Analysis of human CRC specimens (TMA) correlating SphK2 and DPD levels.
- Utilized genetically modified mouse models (villin-SphK2 Tg, SphK2-/-) and xenograft models.
- Employed Chromatin Immunoprecipitation sequencing (ChIP-Seq) and luciferase reporter assays.
- Tested SphK2 inhibitor SLR080811 in vivo.
Main Results:
- High SphK2 expression positively correlated with increased DPD in human CRC tissues.
- High SphK2 upregulates DPD via HDAC1-mediated H3K56 acetylation, promoting 5-FU degradation.
- SphK2 inhibition by SLR080811 reduced DPD expression and reversed 5-FU resistance in mouse models.
Conclusions:
- SphK2 upregulation of DPD represents a novel mechanism of 5-FU resistance in CRC.
- Targeting SphK2 offers a potential therapeutic strategy to enhance 5-FU efficacy in colorectal cancer.
- This study provides a basis for developing combination therapies involving SphK2 inhibitors and 5-FU.
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