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Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca²⁺ Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

ABSTRACT: Several new therapeutic options emerged recently to treat metastatic melanoma; however, the high frequency of intrinsic and acquired resistance among patients shows a need for new therapeutic options. Previously, we identified the plasma membrane Ca²⁺ ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells. Earlier it was also demonstrated that histone deacetylase inhibitors (HDACis) upregulated PMCA4b expression in gastric, colon, and breast cancer cells. In this study, we treated one BRAF wild-type and two BRAF-mutant melanoma cell lines with the HDACis, SAHA and valproic acid, either alone, or in combination with the BRAF inhibitor, vemurafenib. We found that HDACi treatment strongly increased the expression of PMCA4b in all cell lines irrespective of their BRAF mutational status, and this effect was independent of ERK activity. Furthermore, HDAC inhibition also enhanced the abundance of the housekeeping isoform PMCA1. Combination of HDACis with vemurafenib, however, did not have any additive effects on either PMCA isoform. We demonstrated that the HDACi-induced increase in PMCA abundance was coupled to an enhanced [Ca²⁺]_i clearance rate and also strongly inhibited both the random and directional movements of A375 cells. The primary role of PMCA4b in these characteristic changes was demonstrated by treatment with the PMCA4-specific inhibitor, caloxin 1c2, which was able to restore the slower Ca²⁺ clearance rate and higher motility of the cells. While HDAC treatment inhibited cell motility, it decreased only modestly the ratio of proliferative cells and cell viability. Our results show that in melanoma cells the expression of both PMCA4b and PMCA1 is under epigenetic control and the elevation of PMCA4b expression either by HDACi treatment or by the decreased activation of the BRAF-MEK-ERK pathway can inhibit the migratory capacity of the highly motile A375 cells.

SUBMITTER: Hegedus L

PROVIDER: S-EPMC5442207 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca<sup>2+</sup> Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

Hegedüs Luca L Padányi Rita R Molnár Judit J Pászty Katalin K Varga Karolina K Kenessey István I Sárközy Eszter E Wolf Matthias M Grusch Michael M Hegyi Zoltán Z Homolya László L Aigner Clemens C Garay Tamás T Hegedüs Balázs B Tímár József J Kállay Enikö E Enyedi Ágnes Á

Frontiers in oncology 20170524

Several new therapeutic options emerged recently to treat metastatic melanoma; however, the high frequency of intrinsic and acquired resistance among patients shows a need for new therapeutic options. Previously, we identified the plasma membrane Ca<sup>2+</sup> ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells. Earlier it was ...[more]

PMID: 28596940

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Project description:BackgroundDiversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6 A modifications in the regulation of tumorigenesis of ocular melanoma.MethodsHistone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6 A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m6 A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m6 A levels of FAT4 were affected.ResultsFirst, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6 A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6 A modification in tumorigenesis.ConclusionsThese results demonstrate that HDACis exert anti-cancer effects by orchestrating m6 A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.

Dataset Information

Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca²⁺ Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

Publications

Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca<sup>2+</sup> Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

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Dataset Information

Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca2+ Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

Publications

Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca<sup>2+</sup> Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca²⁺ Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK.