Browsing by Author "Niu, Yi"

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    Loss‐of‐Function Genetic Screening Identifies Aldolase A as an Essential Driver for Liver Cancer Cell Growth Under Hypoxia
    (Wolters Kluwer, 2021-09) Niu, Yi; Lin, Ziyou; Wan, Arabella; Sun, Lei; Yan, Shijia; Liang, Heng; Zhan, Siyue; Chen, Dongshi; Bu, Xianzhang; Liu, Peiqing; Chen, Ceshi; He, Weiling; Lu, Xiongbin; Wan, Guohui; Medical and Molecular Genetics, School of Medicine
    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-1α and fat mass and obesity-associated protein-mediated N6 -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.
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    N 6-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development
    (Elsevier, 2018-10) Niu, Yi; Wan, Arabella; Lin, Ziyou; Lu, Xiongbin; Wan, Guohui; Medical and Molecular Genetics, School of Medicine
    N 6-Methyladenosine (m6A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6A modification methyltransferase, demethylase and proteins that preferentially recognize m6A modification as "writers", "erasers" and "readers", respectively. Altered expression levels of the m6A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6A modification regulators for cancer drug development.