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A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo

ABSTRACT: Jumonji C-domain containing protein 6 (JMJD6), an iron (Fe2+) and a-ketoglutarate (a-KG)-dependent oxygenase, is expressed at high levels, correlated with poor prognosis, and considered as a therapeutic target in multiple cancer types. However, specific JMJD6 inhibitors that are potent in suppressing tumorigenesis have not been reported so far. We herein report that iJMJD6, a specific small-molecule inhibitor of JMJD6 with favorable physiochemical properties, inhibits the enzymatic activity of JMJD6 protein both in vitro and in cultured cells. iJMJD6 is effective in suppressing cell proliferation, migration, and invasion in multiple types of cancer cells in a JMJD6-dependent manner, while it exhibits minimal toxicity in normal cells. Mechanistically, iJMJD6 represses the expression of oncogenes including Myc and CCND1, in accordance with JMJD6 function in promoting the transcription of these genes. iJMJD6 exhibits suitable pharmacokinetic properties and suppresses tumor growth in multiple cancer cell line-and patient-derived xenograft models with safety. Furthermore, combination therapy with iJMJD6 and BET protein inhibitor (BETi) JQ1 or estrogen receptor antagonist fulvestrant exhibits synergistic effects in suppressing tumor growth. Taken together, we demonstrate that inhibition of JMJD6 enzymatic activity by using iJMJD6 is effective in suppressing oncogene expression and cancer development, providing a therapeutic avenue for treating cancers that are dependent on JMJD6 in clinic.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201988 | GEO | 2022/08/31

REPOSITORIES: GEO

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Project description:The Jumonji domaining-containing protein JMJD6 is a 2-oxoglutarate dependent dioxygenase that has been implicated in a broad range of biological functions. Cellular studies have implicated the enzyme in chromatin biology, transcription, DNA repair, mRNA splicing and co-transcriptional processing. Although not all studies agree, JMJD6 has been reported to catalyse both hydroxylation of lysine residues and demethylation of arginine residues. However, despite extensive study and the indirect implication of JMJD6 catalysis in many cellular processes, direct assignment of JMJD6 catalytic substrates has been limited. Examination of a site of reported prolyl hydroxylation within a lysine-rich region of the bromodomain protein BRD4 led us to conclude that hydroxylation was in fact on lysine and catalysed by Jmjd6. This prompted a wider search for JMJD6-catalysed protein modifications deploying mass spectrometric methods designed to identify novel substrate associations and facilitate analysis of lysine-rich regions by LC-MSMS. Using derivatization of lysine with propionic anhydride to improve the analysis of tryptic peptides and a pharmacological inhibitor of JMJD6 to stabilise enzyme/substrate associations, we report over 100 sites of JMJD6-catalysed lysyl hydroxylation on 48 protein substrates including 19 sites of hydroxylation on BRD4. Most hydroxylations were within lysine-rich regions that are predicted to be unstructured; in some multiple modifications were observed on adjacent lysine residues. Almost all of the JMJD6 substrates defined in this study have been associated with membraneless organelle formation. Taken together with findings implicating lysine-rich regions in subcellular partitioning by liquid-liquid phase separation, our findings raise the possibility that JMJD6 may play a role in regulating such processes in response to stresses, including hypoxia. Note, this dataset corresponds to Figure 3 of the published manuscript; which employs a substrate-trapping methodology to identify novel substrates of JMJD6 by label free DIA approach.

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A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo

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