Squalene epoxidase promotes colorectal cancer cell proliferation through accumulating calcitriol and activating CYP24A1-mediatedMAPK signaling  

作　　者：Luwei He Huaguang Li Chenyu Pan Yutong Hua Jiayin Peng Zhaocai Zhou Yun Zhao Moubin Lin 

机构地区：[1]Center for Clinical Research and Translational Medicine,Yangpu Hospital,Tongji University School of Medicine,Shanghai 200090,P.R.China [2]Institute of Gastrointestinal Surgery and Translational Medicine,Tongji University School of Medicine,Shanghai 200090,P.R.China [3]Department of General Surgery,Yangpu Hospital,Tongji University School of Medicine,Shanghai 200090,P.R.China [4]The State Key Laboratory of Cell Biology,CAS Center for Excellence in Molecular Cell Science,Shanghai Institute of Biochemistry and Cell Biology,University of Chinese Academy of SciencesChinese Academy of Sciences,Shanghai 200031,P.R.China [5]State Key Laboratory of Genetic Engineering,School of Life Sciences,Zhongshan Hospital,Fudan University,Shanghai 200438,P.R.China [6]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,P.R.China

出　　处：《Cancer Communications》2021年第8期726-746,共21页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Numbers:31630047,81874201,81725014;Natural Science Foundation of Shanghai,Grant/AwardNumber:20ZR1452300;Shanghai Municipal Health Bureau,Grant/Award Number:201840359;The National Key Research and Development Program of China,Grant/Award Numbers:2020YFA0509000,2017YFA0503600。

摘　　要：Background:Colorectal cancer(CRC)is one of the most malignant tumorswith high incidence,yet its molecular mechanism is not fully understood,hindering the development of targeted therapy.Metabolic abnormalities are a hallmark of cancer.Targeting dysregulated metabolic features has become an important direction for modern anticancer therapy.In this study,we aimed to identify a new metabolic enzyme that promotes proliferation of CRC and to examine the related molecular mechanisms.Methods:We performed RNA sequencing and tissue microarray analyses of human CRC samples to identify new genes involved in CRC.Squalene epoxidase(SQLE)was identified to be highly upregulated in CRC patients.The regulatory function of SQLE in CRC progression and the therapeutic effect of SQLE inhibitors were determined by measuring CRC cell viability,colony and organoid formation,intracellular cholesterol concentration and xenograft tumor growth.Themolecularmechanism of SQLE functionwas explored by combining transcriptome and untargeted metabolomics analysis.Western blotting and realtime PCR were used to assess MAPK signaling activation by SQLE.Results:SQLE-related control of cholesterol biosynthesis was highly upregulated in CRC patients and associated with poor prognosis.SQLE promoted CRC growth in vitro and in vivo.Inhibition of SQLE reduced the levels of calcitriol(active form of vitamin D3)and CYP24A1,followed by an increase in intracellular Ca2+concentration.Subsequently,MAPK signaling was suppressed,resulting in the inhibition of CRC cell growth.Consistently,terbinafine,an SQLE inhibitor,suppressed CRC cell proliferation and organoid and xenograft tumor growth.Conclusions:Our findings demonstrate that SQLE promotes CRC through the accumulation of calcitriol and stimulation of CYP24A1-mediated MAPK signaling,highlighting SQLE as a potential therapeutic target for CRC treatment.

关 键 词：CALCITRIOL cell proliferation cholesterol biosynthesis colorectal cancer CYP24A1 MAPK signaling squalene epoxidase TERBINAFINE 

分 类 号：R73[医药卫生—肿瘤]