SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression
SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression
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SphK2 通过上调 H3K56ac 介导的 DPD 表达赋予结直肠癌 5-氟尿嘧啶耐药性
DOI：
10.1038/s41388-020-1352-y
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发表时间：
2020-06
期刊：
影响因子：
8
通讯作者：
Xian-Jun Qu
中科院分区：
文献类型：
--
作者：
Yu-Hang Zhang;Wen-Na Shi;Shu-hua Wu;Rong-Rong Miao;Shi-Yue Sun;Dong-Dong Luo;Sheng-Biao Wan;Zhi-Kun Guo;Wen-Yu Wang;Xin-Feng Yu;Shu-Xiang Cui;Xian-Jun Qu
神经鞘脂代谢异常与化疗耐药有关，但其潜在机制仍不甚清楚。在此，我们揭示了结直肠癌(CRC)中SphK2上调的二氢嘧啶脱氢酶(DPD)高表达导致5-氟尿嘧啶(5-FU)耐药的一个先前未知的机制，这一机制在人类结直肠癌标本、动物模型和癌细胞株中得到了证实。从随机选择的60例结直肠癌标本中，首次确定了SphK2升高和DPD增加之间的临床相关性(p<；0.001)。在此基础上，探讨了其在绒毛蛋白-SphK2TG小鼠、SphK2−/−小鼠和人结直肠癌细胞裸鼠移植瘤模型中的调控机制。ChIP-Seq和荧光素酶报告基因分析表明，高SphK2通过促进HDAC1介导的H3K56ac上调DPD，导致细胞内5-FU降解为无活性的α-flo-β-alanine(FBAL)。最后，SLR080811对SphK2的抑制对DPD的表达有很好的抑制作用，并有效地逆转了Villin-SphK2 TG小鼠对5-FU的耐药性。总体而言，本研究表明，SphK2高表达通过上调肿瘤DPD而产生5-FU耐药，这突出了阻断SphK2以克服结直肠癌5-FU耐药的策略。
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.
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DOI：
10.1186/s13046-015-0205-y
发表时间：
2015-09-04
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Xun C;Chen MB;Qi L;Tie-Ning Z;Peng X;Ning L;Zhi-Xiao C;Li-Wei W
通讯作者：
Li-Wei W
影响因子：
5.7
作者：
Venant H;Rahmaniyan M;Jones EE;Lu P;Lilly MB;Garrett-Mayer E;Drake RR;Kraveka JM;Smith CD;Voelkel-Johnson C
通讯作者：
Voelkel-Johnson C
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
24.5
作者：
Rosmarin D;Palles C;Pagnamenta A;Kaur K;Pita G;Martin M;Domingo E;Jones A;Howarth K;Freeman-Mills L;Johnstone E;Wang H;Love S;Scudder C;Julier P;Fernández-Rozadilla C;Ruiz-Ponte C;Carracedo A;Castellvi-Bel S;Castells A;Gonzalez-Neira A;Taylor J;Kerr R;Kerr D;Tomlinson I
通讯作者：
Tomlinson I
DOI：
10.1158/1078-0432.ccr-16-2363
发表时间：
2017-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Britten CD;Garrett-Mayer E;Chin SH;Shirai K;Ogretmen B;Bentz TA;Brisendine A;Anderton K;Cusack SL;Maines LW;Zhuang Y;Smith CD;Thomas MB
通讯作者：
Thomas MB