期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2200753119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
JMJD6 is overexpressed in multiple types of cancers and promotes tumorigenesis. The enzymatic activity of JMJD6 is often tightly linked to its cellular functions. Thus, development of effective inhibitors specifically targeting JMJD6 enzymatic activity is of great interest to treat cancers. Our results demonstrate that iJMJD6 is a specific small-molecule inhibitor targeting the enzymatic activity of JMJD6, and is potent in suppressing oncogene expression and cancer development. iJMJD6 therefore might serve as a great tool for further exploring JMJD6's function in both physiological and pathological processes and provide a promising therapeutic approach for treating JMJD6-driven cancers.
Jumonji C-domain-containing protein 6 (JMJD6), an iron (Fe
2+) and α-ketoglutarate (α-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 safely. 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 the clinic.
