Targeting histone demethylase KDM5B for cancer treatment

Minyuan, Huang; Guo, Jiawen; You, Ya-Zhen; Liu, Hong‐Min; Huang, Le Hui

doi:10.1016/j.ejmech.2020.112760

Cited by 27 publications

(21 citation statements)

References 116 publications

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“…KDM5B downregulates the oncogenic potential of leukemic stem cells by inducing H3K4-specific demethylation in murine and human MLL-rearranged AML cells, thereby promoting cell differentiation (16). Indeed, the KDM5B protein is the target of various inhibitors that are under study for the treatment of cancer (17). In the same line, the oncogene LAPTM4B (Lysosomal Protein Transmembrane 4 Beta) plays several roles in carcinogenesis, such as promoting tumor growth and metastasis, inhibiting apoptosis, initiating autophagy and driving multidrug resistance mechanisms (18).…”

Section: Discussionmentioning

confidence: 99%

Personalized Survival Prediction of Patients With Acute Myeloblastic Leukemia Using Gene Expression Profiling

et al. 2021

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Acute Myeloid Leukemia (AML) is a heterogeneous neoplasm characterized by cytogenetic and molecular alterations that drive patient prognosis. Currently established risk stratification guidelines show a moderate predictive accuracy, and newer tools that integrate multiple molecular variables have proven to provide better results. In this report, we aimed to create a new machine learning model of AML survival using gene expression data. We used gene expression data from two publicly available cohorts in order to create and validate a random forest predictor of survival, which we named ST-123. The most important variables in the model were age and the expression of KDM5B and LAPTM4B, two genes previously associated with the biology and prognostication of myeloid neoplasms. This classifier achieved high concordance indexes in the training and validation sets (0.7228 and 0.6988, respectively), and predictions were particularly accurate in patients at the highest risk of death. Additionally, ST-123 provided significant prognostic improvements in patients with high-risk mutations. Our results indicate that survival of patients with AML can be predicted to a great extent by applying machine learning tools to transcriptomic data, and that such predictions are particularly precise among patients with high-risk mutations.

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Section: Discussionmentioning

confidence: 99%

Personalized Survival Prediction of Patients With Acute Myeloblastic Leukemia Using Gene Expression Profiling

et al. 2021

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“…Hepatocyte KDM5B was predicted to be activated by alcohol in male mice and inhibited in female mice. Given its role in tumor development, ( 9,10 ) KDM5B activation in male mice could contribute to alcohol‐induced hepatocyte dedifferentiation.…”

Section: Resultsmentioning

confidence: 99%

Male‐Specific Activation of Lysine Demethylases 5B and 5C Mediates Alcohol‐Induced Liver Injury and Hepatocyte Dedifferentiation

et al. 2022

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Alcohol‐associated liver disease (ALD) is a major cause of alcohol‐related mortality. Sex differences in sensitivity to ALD are well described, but these are often disregarded in studies of ALD development. We aimed to define sex‐specific pathways in liver exposed to alcohol. Mice were fed the Lieber‐DeCarli alcohol liquid diet or a combination of a high‐fat diet with alcohol in water. Single‐cell RNA sequencing (scRNA‐Seq) was performed on liver cells from male and female mice. Mice were treated with adeno‐associated virus (AAV)‐short hairpin (sh)Control or AAV‐sh lysine demethylase 5b (shKdm5b) and/or AAV‐shKdm5c vectors. Changes after Kdm5b/5c knockdown were assessed by RNA‐Seq and histone H3 lysine K4 (H3K4)me3 chromatin immunoprecipitation‐Seq analysis. Using scRNA‐Seq analysis, we found several sex‐specific pathways induced by alcohol, including pathways related to lipid metabolism and hepatocyte differentiation. Bioinformatic analysis suggested that two epigenetic regulators, H3K4‐specific lysine demethylases KDM5B and KDM5C, contribute to sex differences in alcohol effects. We found that in alcohol‐fed male mice, KDM5B and KDM5C are involved in hepatocyte nuclear factor 4 alpha (Hnf4a) down‐regulation, hepatocyte dedifferentiation, and an increase in fatty acid synthesis. This effect is mediated by alcohol‐induced KDM5B and KDM5C recruitment to Hnf4a and other gene promoters in male but not in female mice. Kdm5b and Kdm5c knockdown or KDM5‐inhibitor treatment prevented alcohol‐induced lipid accumulation and restored levels of Hnf4a and other hepatocyte differentiation genes in male mice. In addition, Kdm5b knockdown prevented hepatocellular carcinoma development in male mice by up‐regulating Hnf4a and decreasing tumor cell proliferation. Conclusion: Alcohol specifically activates KDM5 demethylases in male mice to promote alcohol‐induced hepatocyte dedifferentiation and tumor development.

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“…Targeted inhibition of KDM5B might be considered in combination of anti-vascular therapy in GC. As KDM5B was upregulated to play an oncogenic role in multiple cancers, many chemical inhibitors of KDM5B have been extensively evaluated for their potential in targeted therapy of human cancer (Zheng et al, 2019;Fu et al, 2020). The combination of these inhibitors with anti-vascular therapy could be taken into consideration while designing upcoming clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

Zhou

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia is an important characteristic of the tumor microenvironment. Tumor cells can survive and propagate under the hypoxia stress by activating a series of adaption response. Herein, we found that lysine-specific demethylase 5B (KDM5B) was upregulated in gastric cancer (GC) under hypoxia conditions. The genetic knockdown or chemical inhibition of KDM5B impaired the growth of GC cell adapted to hypoxia. Interestingly, the upregulation of KDM5B in hypoxia response was associated with the SUMOylation of KDM5B. SUMOylation stabilized KDM5B protein by reducing the competitive modification of ubiquitination. Furthermore, the protein inhibitor of activated STAT 4 (PIAS4) was determined as the SUMO E3 ligase, showing increased interaction with KDM5B under hypoxia conditions. The inhibition of KDM5B caused significant downregulation of hypoxia-inducible factor-1α (HIF-1α) protein and target genes under hypoxia. As a result, co-targeting KDM5B significantly improved the antitumor efficacy of antiangiogenic therapy in vivo. Taken together, PIAS4-mediated SUMOylation stabilized KDM5B protein by disturbing ubiquitination-dependent proteasomal degradation to overcome hypoxia stress. Targeting SUMOylation-dependent KDM5B upregulation might be considered when the antiangiogenic therapy was applied in cancer treatment.

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Targeting histone demethylase KDM5B for cancer treatment

Cited by 27 publications

References 116 publications

Personalized Survival Prediction of Patients With Acute Myeloblastic Leukemia Using Gene Expression Profiling

Personalized Survival Prediction of Patients With Acute Myeloblastic Leukemia Using Gene Expression Profiling

Male‐Specific Activation of Lysine Demethylases 5B and 5C Mediates Alcohol‐Induced Liver Injury and Hepatocyte Dedifferentiation

Hypoxia Stimulates SUMOylation-Dependent Stabilization of KDM5B

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