A Coding Single-Nucleotide Polymorphism in Lysine Demethylase KDM4A Associates with Increased Sensitivity to mTOR Inhibitors

Abstract

SUMMARY Single nucleotide polymorphisms (SNPs) occur within chromatin-modulating factors; however, little is known about how these variants within the coding sequence impact cancer progression or treatment. Therefore, there is a need to establish their biochemical and/or molecular contribution, their use in sub-classifying patients and their impact on therapeutic response. In this report, we demonstrate that coding SNP-A482 within the lysine tri-demethylase KDM4A/JMJD2A has different allelic frequencies across ethnic populations, associates with differential outcome in non-small cell lung cancer (NSCLC) patients and promotes KDM4A protein turnover. Using an unbiased drug screen against 87 preclinical and clinical compounds, we demonstrate that homozygous SNP-482 cells have increased mTOR inhibitor sensitivity. mTOR inhibitors significantly reduce SNP-A482 protein levels, which parallels the increased drug sensitivity observed with KDM4A depletion. Our data emphasize the importance of using variant status as candidate biomarkers and highlight the importance of studying SNPs in chromatin modifiers to achieve better targeted therapy.

KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes

“…Although KDM4A, 4B, and 4C are shown to be overexpressed in many human cancers and promote tumorigenesis through variety of mechanisms (1, 6, 27, 28), the mechanism by which KDM4B activates PLK1 transcription via BMYB in the late S-phase of PCa cells has not been reported before, thus we focused on this mechanism in this study. We found that KDM4B is the major isoform in PCa tumorigenesis compared to KDm4A and 4C.…”

“…Both PLK1 and BMYB are implicated in human tumorigenesis (22, 23, 27–29). PLK1 is a critical regulator for both DNA replication and chromosome segregation in mitosis (24, 29).…”

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

“…Recently, Van Rechem et al. reported that single‐nucleotide polymorphisms within the KDM4A gene are associated with increased mTOR inhibitor sensitivity and with worse outcome in patients with non‐small‐cell lung cancer (NSCLC) …”

Tetrazolylhydrazides as Selective Fragment‐Like Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

“…[10] At this point, the readeri sr eferred to the extensive and in-depth reviewso fK DM4A's complex role in cancer by Hoffmann et al [9] and Guerra-Calderas et al [11] While there seems to be ag eneral trend regarding the correlation between elevated KDM4Ae xpression levelsa nd cancer, the opposite was observed as well. This picture is even further complicated by the influence of single-nucleotide polymorphisms within the KDM4A gene, as recently reported by VanRechem et al [12] Thus, the definite role of this enzyme in oncogenesisremains to be determined.…”