Histone deacetylase inhibitors induce invasion of human melanoma cells in vitro via differential regulation of N-cadherin expression and RhoA activity

Díaz-Núñez, María; Díez-Torre, Alejandro; Wever, Olivier De; Andrade, Ricardo; Arluzea, Jon; Silio, Margarita; Aréchaga, Juan

doi:10.1186/s12885-016-2693-3

Cited by 20 publications

(20 citation statements)

References 48 publications

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“…Detailed analysis of the effects of SAHA-loaded nanoparticles on EMT transition markers revealed a signi cant upregulated E-cadherin expression, but with no affect N-cadherin expression. This is consistent with previous studies, where HDACi were shown to have only a slight effect on N-cadherin expression in HT-144 and A375 cells [58]. E-cadherins mediate intercellular adhesion through the interaction of the extracellular and cytoplasmic domains with β-catenin.…”

Section: Discussionsupporting

confidence: 93%

Nanomicelles Potentiate HDAC Inhibitor Efficacy In Vitro.

Pisano

Wang

et al. 2020

Preprint

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Background. Amphiphilic block copolymers used as nanomicelle drug carriers can effectively overcome poor drug solubility and specificity issues. Hence, these platforms have a broad applicability in cancer treatment. In this study, Pluronic F127 was used to fabricate nanomicelles containing the histone deacetylase inhibitor SAHA, which has an epigenetic-driven anti-cancer effect in several tumor types. SAHA loaded nanomicelles were prepared using a thin-film drying method and characterized for size, surface charge, drug content and drug release properties. Loaded particles were tested for in vitro activity and their effect on cell-cycle and markers of metastasis. Results. Following detailed particle characterization, cell proliferation experiments demonstrated that SAHA loaded nanomicelles more effectively inhibited the growth of HeLa and MCF-7 cell lines compared with free drug formulations. The 30nm SAHA containing nanoparticles were able to release up to 100% of the encapsulated drug over a 72h time window. Moreover, gene and protein expression analyses suggested that this effect was achieved through the regulation of p21 and p53 expression. SAHA was also shown to upregulate E-cadherin expression, potentially influencing tumor migration and metastasis.Conclusions. This study highlights the opportunity to exploit pluronic-based nanomicelles for the delivery of compounds that regulate epigenetic processes, thus inhibiting cancer development and progression.

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Section: Discussionsupporting

confidence: 93%

Nanomicelles Potentiate HDAC Inhibitor Efficacy In Vitro.

Pisano

Wang

et al. 2020

Preprint

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“…It is possible that RhoA and Rac1 were also regulated by histone deacetylase. (49)(50)(51) In this case, it is hard to prove the overall hypothetical mechanism that overexpression of SchLAH could downregulate RhoA and Rac1 by TSA treatment. However, mechanisms of SchLAH downregulation in HCC needs to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma

Cheng

Yang

et al. 2017

Cancer Science

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Emerging evidence has indicated that deregulation of long non‐coding RNAs (lncRNAs) can contribute to the progression and metastasis of human cancer, including hepatocellular carcinoma (HCC). However, the roles of most lncRNAs in HCC remain largely unknown. Here we found a long noncoding RNA termed SchLAH (seven chromosome locus associated with HCC; also called BC035072) was generally downregulated in HCC. Low expression of SchLAH was significantly correlated with shorter overall survival of HCC patients. In vitro and in vivo assays indicated that overexpression of SchLAH inhibited the migration and lung metastasis of HCC cells. Knockdown of SchLAH by siRNA pool promoted the migration of HCC cells. RNA pull‐down and RNA immunoprecipitation assays demonstrated SchLAH physically interacted with fused in sarcoma (FUS). PCR array analysis showed that RhoA and Rac1 were the downstream effector molecules of SchLAH during HCC metastasis. Knockdown of FUS rescued the mRNA levels of RhoA and Rac1 that were repressed by SchLAH. These results suggest that SchLAH may suppress the metastasis of HCC cells by interacting with FUS, which indicates potential of SchLAH for the prognosis and treatment of HCC.

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“…SUR cell spheroids treated with HDAC inhibitors may exhibit invasive behaviour, with morphology suggestive of an invasive phenotype. It has been previously demonstrated that several HDAC inhibitors, such as SAHA, TSA, valproic acid and sodium butyrate, promote melanoma cell invasion in vitro via the upregulation of N-cadherin and inhibition of Ras homolog A activity (34). Using flow cytometry, it was found that parental and SUR cell spheroids treated with MGCD0103 alone or in combination with PLX4032 for 72 h had significantly reduced viability, whereas PLX4032 treatment alone did not lead to significant loss of viability (Fig S4D; Fig.…”

Section: Sensitivity Of Sur Cells To Epigenetic Inhibitorsmentioning

confidence: 99%

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

et al. 2020

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It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.

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Histone deacetylase inhibitors induce invasion of human melanoma cells in vitro via differential regulation of N-cadherin expression and RhoA activity

Cited by 20 publications

References 48 publications

Nanomicelles Potentiate HDAC Inhibitor Efficacy In Vitro.

Nanomicelles Potentiate HDAC Inhibitor Efficacy In Vitro.

Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

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