KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells

Metzger, Eric; Wang, Sheng; Urban, Sylvia; Willmann, Dominica; Schmidt, Andreas; Offermann, Anne; Allen, Anita L.; Sum, Manuela; Obier, Nadine; Cottard, Félicie; Ulferts, Svenja; Preca, Bogdan‐Tiberius; Hermann, B. A.; Maurer, Jochen; Greschik, Holger; Hornung, Veit; Einsle, Oliver; Imhof, Axel; Jung, Manfred; Schüle, Roland

doi:10.1038/s41594-019-0219-9

Cited by 62 publications

(138 citation statements)

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“…Since KMT9 has been shown to regulate gene expression [9] we next performed global transcriptome analyses (RNA-Seq) in A549 cells treated with siControl or siKMT9α#1 and identified 6614 differentially expressed genes upon KMT9α knock-down ( Fig. 2a).…”

Section: Resultsmentioning

confidence: 99%

“…Until recently, all known histone lysine methyl transferases belonged to the su(var)3-9, enhancer-of-zeste and trithorax (SET) domain family with the only exception being DOT1L that belongs to the seven-β-strand family [7,8]. Recently, a second histone lysine methyl transferase of the seven-β-strand family named lysine methyl transferase 9 (KMT9) was described [9]. KMT9 is an heterodimeric enzyme formed by the assembly of KMT9α (also known as C21ORF127, HEMK2 [10,11], MTQ2, N6AMT1 [12], PRMC or PRED28 [13] and KMT9β (also known as TRMT112) [9].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a second histone lysine methyl transferase of the seven-β-strand family named lysine methyl transferase 9 (KMT9) was described [9]. KMT9 is an heterodimeric enzyme formed by the assembly of KMT9α (also known as C21ORF127, HEMK2 [10,11], MTQ2, N6AMT1 [12], PRMC or PRED28 [13] and KMT9β (also known as TRMT112) [9]. KMT9 mono methylates lysine 12 of histone 4 (H4K12me1) in vitro and in vivo thereby controlling proliferation of prostate tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…In prostate tumor cells, KMT9 was found enriched at promoters of numerous cell cycle regulators and it has been shown that KMT9 controls cell cycle progression. KMT9 depletion severely affects proliferation of androgen receptor-dependent as well as castration-and enzalutamide-resistant prostate cancer cells and xenograft tumors [9]. Yet, the function of KMT9 in lung cancer cells has remained elusive.…”

Section: Introductionmentioning

confidence: 99%

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Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

et al. 2020

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Background: Lung cancer is the leading cause of cancer related death worldwide. Over the past 15 years no major improvement of survival rates could be accomplished. The recently discovered histone methyltransferase KMT9 that acts as epigenetic regulator of prostate tumor growth has now raised hopes of enabling new cancer therapies. In this study, we aimed to identify the function of KMT9 in lung cancer. Methods:We unraveled the KMT9 transcriptome and proteome in A549 lung adenocarcinoma cells using RNA-Seq and mass spectrometry and linked them with functional cell culture, real-time proliferation and flow cytometry assays. Results:We show that KMT9α and -β subunits of KMT9 are expressed in lung cancer tissue and cell lines. Importantly, high levels of KMT9α correlate with poor patient survival. We identified 460 genes that are deregulated at the RNA and protein level upon knock-down of KMT9α in A549 cells. These genes cluster with proliferation, cell cycle and cell death gene sets as well as with subcellular organelles in gene ontology analysis. Knock-down of KMT9α inhibits lung cancer cell proliferation and induces non-apoptotic cell death in A549 cells. Conclusions:The novel histone methyltransferase KMT9 is crucial for proliferation and survival of lung cancer cells harboring various mutations. Small molecule inhibitors targeting KMT9 therefore should be further examined as potential milestones in modern epigenetic lung cancer therapy. Additional file 5. Certificate NCI-H2087. Results and certificate of STRprofiling and cell authentication. Additional file 6. Certificate CRL-7000. Results and certificate of STRprofiling and cell authentication. "HS 1.Lu" is a synonym of CRL-7000. Additional file 7. Certificate IMR-90. Results and certificate of STR-profiling and cell authentication. Additional file 8. KMT9α expression is significantly increased in stage 1 and 3 lung adenocarcinoma from the TCGA cohort. a TCGA lung adenocarcinoma samples were divided according to stage and the KMT9α expression analyzed. Data represent interquartile range including minimum, 25th percentile, median, 75th percentile and maximum values. Significance was accessed by t test. b TCGA lung adenocarcinoma samples were divided according to histopathologic subtypes and the KMT9α expression analyzed. Data represent interquartile range including minimum, 25th percentile, median, 75th percentile and maximum values. Significance was accessed by t test. Subgroups with p-value < 0.05 when compared to normal are marked by "*". Abbreviations NSCLC: Non-small cell lung cancer; SCLC: Small cell lung cancer; SSC: Side scatter; FSC: Forward scatter; RNA-Seq: RNA sequencing; qRT-PCR: Quantitative real-time polymerase chain reaction. of Cologne,

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

et al. 2020

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“…The treatment of PCa has attracted increasing attention in recent years (12). Previous studies have reported numerous gene targets that were able to inhibit cell proliferation and promote apoptosis in PCa (21)(22)(23). A recent study has suggested that certain natural products, such as green tea, can effectively induce apoptosis and inhibit invasion of PCa cells via the PI3K/Akt signaling pathway (24).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

Lin

et al. 2020

Int J Oncol

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Prostate cancer (PCa) is the second leading cause of cancer-related death among men worldwide. The present study aimed to investigate the role of germ cell-specific gene 2 protein (GSG2), also termed histone H3 phosphorylated by GSG2 at threonine-3, in the development and progression of PCa. GSG2 expression levels in PCa tissues and para-carcinoma tissues was detected by immunohistochemistry. The GSG2 knockdown cell model was constructed by lentivirus infection, and the knockdown efficiency was verified by qPCR and WB. In addition, the effects of shGSG2 on cell proliferation, colony formation and apoptosis were evaluated by Celigo cell counting assay, Giemsa staining and flow cytometry, respectively. Tumor development in nude mice was also detected. GSG2 expression was upregulated in PCa tissues and human PCa cell lines PC-3 and DU 145. High expression of GSG2 in tumor samples was associated with progressed tumors. GSG2 knockdown suppressed cell proliferation and colony formation, but promoted apoptosis, which was also verified in vivo.The results of the present study revealed that GSG2 upregulation was associated with PCa progression; GSG2 knockdown inhibited cell proliferation and colony formation and induced apoptosis, and may therefore serve as a potential therapeutic target for PCa therapy.

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Advances and Opportunities in Epigenetic Chemical Biology

2020

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The study of epigenetics has greatly benefited from the development and application of various chemical biology approaches. In this review, we highlight the key targets for modulation and recent methods developed to enact such modulation. We discuss various chemical biology techniques to study DNA methylation and the post-translational modification of histones as well as their effect on gene expression. Additionally , we address the wealth of protein synthesis approaches to yield histones and nucleosomes bearing epigenetic modifications. Throughout, we highlight targets that present opportunities for the chemical biology community, as well as exciting new approaches that will provide additional insight into the roles of epigenetic marks.

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KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells

Cited by 62 publications

References 45 publications

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death

Knockdown of GSG2 inhibits prostate cancer progression in�vitro and in�vivo

Advances and Opportunities in Epigenetic Chemical Biology

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