Genome-wide CRISPR Screening Reveals Pyrimidine Metabolic Reprogramming in 5-FU Chronochemotherapy of Colorectal Cancer.
Genome-wide CRISPR Screening Reveals Pyrimidine Metabolic Reprogramming in 5-FU Chronochemotherapy of Colorectal Cancer.
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全基因组 CRISPR 筛选揭示结直肠癌 5-FU 计时化疗中的嘧啶代谢重编程
DOI：
10.3389/fonc.2022.949715
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发表时间：
2022
影响因子：
4.7
通讯作者：
Lu, Chao
中科院分区：
文献类型：
--
作者：
Niu, Ya;Fan, Xinyi;Wang, Yaping;Lin, Jiaxin;Hua, Luchun;Li, Xiaobo;Qian, Ruizhe;Lu, Chao
Disruption of the circadian rhythm is associated with cancer occurrence, response to chemotherapy, and poor prognosis. Thus, using internal clock-based chronotherapy to optimize the administration time may improve the therapeutic effects of anticancer drugs while reducing the side effects. Chronotherapy with 5-fluorouracil (5-FU) has been observed in colorectal cancer (CRC) for a long time, but its effect is under controversial and the mechanism remains unclear. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening and RNA-sequencing were combined to identify the potential genes or pathways involved in 5-FU chronochemotherapy. Genetic deletion or overexpression of pyrimidine metabolic pathway genes were conducted to examine cellular viability with or without 5-FU via flow cytometry. Western blotting, qPCR, chromatin immunoprecipitation, gain-of-function and loss-of-function assays of several CRC cell lines in vitro and in vivo were used to elaborate and validate the mechanism of 5-FU chronotherapeutic effects. Chronochemotherapeutic effects of 5-FU on CRC in vivo were verified. Furthermore, 5-FU chronochemotherapy related genes such as UPP2, UCK2 and UMPS in the pyrimidine metabolic pathway were identified. Disturbance in these genes, especially UMPS, perturbs 5-FU treatment outcomes in CRC cells. Mechanistically, the core circadian gene, brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1), extensively regulate gene expression in pyrimidine metabolic pathway by binding to E-box element in the promoter region of key genes such as UMPS and perturb their enzymatic activities, thereby maintain diurnal efficacy of 5-FU in CRC cells. This study uncovered a new mechanism by which a core circadian gene BMAL1 increases the effectiveness of 5-FU by enhancing the expression and enzymatic activities of key genes in the pyrimidine metabolic pathway in CRC cells. The findings suggest a novel strategy for CRC chemotherapy by targeting chrono-modulated genes of the 5-FU metabolic pathway.
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影响因子：
8
作者：
Battaglin F;Chan P;Pan Y;Soni S;Qu M;Spiller ER;Castanon S;Roussos Torres ET;Mumenthaler SM;Kay SA;Lenz HJ
通讯作者：
Lenz HJ
影响因子：
11.2
作者：
Shafi AA;Knudsen KE
通讯作者：
Knudsen KE
影响因子：
14.9
作者：
Pizarro A;Hayer K;Lahens NF;Hogenesch JB
通讯作者：
Hogenesch JB
影响因子：
11.1
作者：
Burgermeister, Elke;Battaglin, Francesca;Ebert, Matthias P.
通讯作者：
Ebert, Matthias P.
影响因子：
64.5
作者：
Balsalobre, A;Damiola, F;Schibler, U
通讯作者：
Schibler, U