Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia

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	Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia
	Niu, Y; Lin, ZY; Wan, A; Sun, L; Yan, SJ; Liang, H; Zhan, SY; Chen, DS; Bu, XZ; Liu, PQ; Chen, CS; He, WL; Lu, XB; Wan, GH
	2021
发表期刊	HEPATOLOGY
ISSN	0270-9139
卷号	74 期号:3 页码:1461-1479
摘要	Background and Aims Hypoxia is a common feature of the tumor microenvironment (TME), which promotes tumor progression, metastasis, and therapeutic drug resistance through a myriad of cell activities in tumor and stroma cells. While targeting hypoxic TME is emerging as a promising strategy for treating solid tumors, preclinical development of this approach is lacking in the study of HCC. Approach and Results From a genome-wide CRISPR/CRISPR-associated 9 gene knockout screening, we identified aldolase A (ALDOA), a key enzyme in glycolysis and gluconeogenesis, as an essential driver for HCC cell growth under hypoxia. Knockdown of ALDOA in HCC cells leads to lactate depletion and consequently inhibits tumor growth. Supplementation with lactate partly rescues the inhibitory effects mediated by ALDOA knockdown. Upon hypoxia, ALDOA is induced by hypoxia-inducible factor-1 alpha and fat mass and obesity-associated protein-mediated N-6-methyladenosine modification through transcriptional and posttranscriptional regulation, respectively. Analysis of The Cancer Genome Atlas shows that elevated levels of ALDOA are significantly correlated with poor prognosis of patients with HCC. In a screen of Food and Drug Administration-approved drugs based on structured hierarchical virtual platforms, we identified the sulfamonomethoxine derivative compound 5 (cpd-5) as a potential inhibitor to target ALDOA, evidenced by the antitumor activity of cpd-5 in preclinical patient-derived xenograft models of HCC. Conclusions Our work identifies ALDOA as an essential driver for HCC cell growth under hypoxia, and we demonstrate that inhibition of ALDOA in the hypoxic TME is a promising therapeutic strategy for treating HCC.
收录类别	sci
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/13691
专题	科研部门_肿瘤生物学（陈策实）
推荐引用方式 GB/T 7714	Niu, Y,Lin, ZY,Wan, A,et al. Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia[J]. HEPATOLOGY,2021,74(3):1461-1479.
APA	Niu, Y.,Lin, ZY.,Wan, A.,Sun, L.,Yan, SJ.,...&Wan, GH.(2021).Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia.HEPATOLOGY,74(3),1461-1479.
MLA	Niu, Y,et al."Loss-of-Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia".HEPATOLOGY 74.3(2021):1461-1479.

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2023032940.pdf（3632KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文