Abstract
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths worldwide. Prostate tumorigenesis and PCa progression involve numerous genetic as well as epigenetic perturbations. Histone modification represents a fundamental epigenetic mechanism that regulates diverse cellular processes, and H3K4 methylation, one such histone modification associated with active transcription, can be reversed by dedicated histone demethylase KDM5B (JARID1B). Abnormal expression and functions of KDM5B have been implicated in several cancer types including PCa. Consistently, our bioinformatics analysis reveals that the KDM5B mRNA levels are upregulated in PCa compared to benign prostate tissues, and correlate with increased tumor grade and poor patient survival, supporting an oncogenic function of KDM5B in PCa. Surprisingly, however, when we generated prostate-specific conditional Kdm5b knockout mice using probasin (Pb) promoter-driven Cre: loxP system, we observed that Kdm5b deletion did not affect normal prostate development but instead induced mild hyperplasia. These results suggest that KDM5B may possess context-dependent roles in normal prostate development vs. PCa development and progression.
Highlights
The American Cancer Society estimates that > 190,000 new cases of prostate cancer (PCa) will be diagnosed in the United States in 2020 along with about 33,330 deaths [1]
We provide evidence that KDM5B, a H3K4 demethylase, may exhibit two contrasting functions: in human PCa, it is significantly upregulated and correlates with poor patient survival pointing to an oncogenic role; in contrast, genetic deletion of Kdm5b leads to mild hyperplasia in the mouse prostate, pointing to a potentially tumorsuppressive function
KDM5B has been traditionally thought to repress transcription since it catalyzes the demethylation of H3K4me1/me2/me3: H3K4me2/me3 are enriched at the promoter region of actively transcribed genes [16] while H3K4me1 marks the enhancer regions [43,44,45]
Summary
The American Cancer Society estimates that > 190,000 new cases of prostate cancer (PCa) will be diagnosed in the United States in 2020 along with about 33,330 deaths [1]. Intratumor heterogeneity is maintained partly through the expression of distinct sets of genes among tumor cells, a phenomenon called cellular transcriptomic heterogeneity (CTH) [4], which is controlled by transcription factors and histone-modifying enzymes [3,4,5,6] These enzymes work through regulating chromatin structure, which is an important determinant of gene activity. Chromatin, consisting of histones wrapped by DNA, is regulated by histone-modifying enzymes via methylation, phosphorylation, acetylation, ubiquitination, sumoylation, and ribosylation at lysine, arginine, serine, threonine, tyrosine, and other residues of histone tails [7, 8] These histone modifications impact gene expression and influence how the 3D structure of the chromatin is organized within the nucleus [9,10,11,12]. Trimethylation of histone 3 at lysine 4 and lysine 36 (H3K4me and H3K36me3) is generally associated with gene activation [15,16,17,18] whereas methylation at lysine 9 and 27 correlates with gene repression [16, 19,20,21]
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