Limits...
Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

Chun SM, Lee JY, Choi J, Lee JH, Hwang JJ, Kim CS, Suh YA, Jang SJ - PLoS ONE (2015)

Bottom Line: Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes.Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation.ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.

ABSTRACT
Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

No MeSH data available.


Related in: MedlinePlus

H4K16 acetylation status adjacent to transcription start site (TSS).H4K16 acetylation adjacent to the TSS was assessed by calculating the average ChIP/input log ratio at the same distance from the TSS. The numbers in the X axis indicate the distance from TSS. Y axis represents the average ChIP/input log ratio. (A) H4K16 acetylation status of genes around TSS was individually depicted in CG200745-treated or untreated Calu6 cells. (B) The level of H4K16 acetylation was compared between CG200745-treated and untreated cells according to the distance from the TSS. Two separate experiments were performed to calculate the error bar for each position.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4363698&req=5

pone.0119379.g004: H4K16 acetylation status adjacent to transcription start site (TSS).H4K16 acetylation adjacent to the TSS was assessed by calculating the average ChIP/input log ratio at the same distance from the TSS. The numbers in the X axis indicate the distance from TSS. Y axis represents the average ChIP/input log ratio. (A) H4K16 acetylation status of genes around TSS was individually depicted in CG200745-treated or untreated Calu6 cells. (B) The level of H4K16 acetylation was compared between CG200745-treated and untreated cells according to the distance from the TSS. Two separate experiments were performed to calculate the error bar for each position.

Mentions: We then examined the pattern of H4K16ac changes according to the distance from the TSS by plotting an average log value of ChIP/input for all probes (Fig. 4), in which the X axis denoted the distance from the TSS area as described in a previous section. The H4K16ac was, surprisingly, decreased at the adjacent area to the TSS, especially at-500 nt from the TSS, after CG200745 treatment, whereas H4K16ac at distant area from TSS was no difference with it in untreated control cells, which is common due to the transcriptional activation function of H4K16 (Fig. 4A). The average log ratio of ChIP/input data clearly demonstrated that fewer genes with H4K16ac at 500 nt from the TSS were seen in treated cells compared to control cells, although a major modification site for H4K16ac was still evident around the TSS (Fig. 4B). These results were confirmed in repeated experiments, indicating that CG200745 treatment suppresses H4K16 acetylation at 500 nt from the TSS of many genes.


Epigenetic modulation with HDAC inhibitor CG200745 induces anti-proliferation in non-small cell lung cancer cells.

Chun SM, Lee JY, Choi J, Lee JH, Hwang JJ, Kim CS, Suh YA, Jang SJ - PLoS ONE (2015)

H4K16 acetylation status adjacent to transcription start site (TSS).H4K16 acetylation adjacent to the TSS was assessed by calculating the average ChIP/input log ratio at the same distance from the TSS. The numbers in the X axis indicate the distance from TSS. Y axis represents the average ChIP/input log ratio. (A) H4K16 acetylation status of genes around TSS was individually depicted in CG200745-treated or untreated Calu6 cells. (B) The level of H4K16 acetylation was compared between CG200745-treated and untreated cells according to the distance from the TSS. Two separate experiments were performed to calculate the error bar for each position.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363698&req=5

pone.0119379.g004: H4K16 acetylation status adjacent to transcription start site (TSS).H4K16 acetylation adjacent to the TSS was assessed by calculating the average ChIP/input log ratio at the same distance from the TSS. The numbers in the X axis indicate the distance from TSS. Y axis represents the average ChIP/input log ratio. (A) H4K16 acetylation status of genes around TSS was individually depicted in CG200745-treated or untreated Calu6 cells. (B) The level of H4K16 acetylation was compared between CG200745-treated and untreated cells according to the distance from the TSS. Two separate experiments were performed to calculate the error bar for each position.
Mentions: We then examined the pattern of H4K16ac changes according to the distance from the TSS by plotting an average log value of ChIP/input for all probes (Fig. 4), in which the X axis denoted the distance from the TSS area as described in a previous section. The H4K16ac was, surprisingly, decreased at the adjacent area to the TSS, especially at-500 nt from the TSS, after CG200745 treatment, whereas H4K16ac at distant area from TSS was no difference with it in untreated control cells, which is common due to the transcriptional activation function of H4K16 (Fig. 4A). The average log ratio of ChIP/input data clearly demonstrated that fewer genes with H4K16ac at 500 nt from the TSS were seen in treated cells compared to control cells, although a major modification site for H4K16ac was still evident around the TSS (Fig. 4B). These results were confirmed in repeated experiments, indicating that CG200745 treatment suppresses H4K16 acetylation at 500 nt from the TSS of many genes.

Bottom Line: Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes.Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation.ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Asan Medical Center, The University of Ulsan College of Medicine, Seoul, Republic of Korea.

ABSTRACT
Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.

No MeSH data available.


Related in: MedlinePlus