Open AccessSmall Molecule‐Induced Differentiation As a Potential Therapy for Liver Cancer
Author(s) -
Zhang Xu,
Zhu XiangJie,
Zhong Zhi,
Du JiangChuan,
Fang GuoXu,
Cui Xiuliang,
Guan LingTing,
Hu YanYu,
Wang HongYang,
Zhang PeiLin
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202103619
Subject(s) - cancer research , reprogramming , cancer cell , cellular differentiation , cancer , cancer stem cell , biology , liver cancer , stem cell , microbiology and biotechnology , chemistry , cell , biochemistry , genetics , gene , hepatocellular carcinoma
Despite the efficacy demonstrated by immunotherapy recently, liver cancer still remains one of the deadliest cancers, mainly due to heterogeneity of this disease. Continuous exploration of new therapeutics is therefore necessary. Chemical‐induced cell differentiation can serve as a promising approach, with its ability to consistently remodel gene expression profile and alter cell fate. Inspired by advances in stem cell and reprogramming field, here it is reported that a small molecule cocktail (SMC) consisted of: SB431542 (TGF β inhibitor), CHIR99021 (GSK3 β inhibitor), BIX01294 (H3K9 methyltransferase/G9a inhibitor), and all‐trans retinoic acid (ATRA), can induce differentiation of liver cancer cells including cell lines, primary cancer cells, cancer stem cells, and drug resistant cells. Treated cells lose malignant characteristics and regain hepatocyte phenotype instead. When applied in vivo, SMC induces wide range of tissue necrosis or fibrosis within the tumors, while remaining tissues begin to express hepatic nuclear factor 4 α (HNF4 α) , the hepatic nuclear marker. SMC also leads to tumor abrogation in orthotopic xenograft models and life span extension of animals. The powerful differentiation induction of SMC is exerted through modulation of Akt/mTOR/HIF1 α signaling and metabolic reprogramming, as well as suppressing Snail and enhancing HNF4 α expression. Together, these results highlight that chemical‐induced differentiation has the potential to effectively treat liver cancer disregard of heterogeneity.