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Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells
Author(s) -
Xu Xin,
Wang Lin,
Hu Linda,
Dirks Wilhelm G.,
Zhao Yao,
Wei Zhishuai,
Chen Dexiang,
Li Zhaoliang,
Wang Zhanju,
Han Yangyang,
Wei Liuya,
Drexler Hans G.,
Hu Zhenbo
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32552
Subject(s) - methylation , microbiology and biotechnology , demethylation , leukemia , haematopoiesis , cell culture , cancer research , chemistry , biology , biochemistry , dna methylation , gene expression , immunology , genetics , gene , stem cell
Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia ( MLL r AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI‐4) and JDI‐12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI‐4 and JDI‐12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI‐4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI‐4 and JDI‐12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI‐4 and JDI‐12 kill MLL r AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI‐16, among multiple compounds structurally akin to JDI‐4/JDI‐12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI‐4/JDI‐12. Mechanistically, JDI‐16 not only induces apoptosis but also differentiation of MLL r AL cells. RNA sequencing and quantitative PCR showed that JDI‐16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI‐16 downregulates lactic acids, NADP + and other metabolites. Moreover, JDI‐16 collaborates with all‐trans retinoic acid to repress MLL r AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLL r AL cells.