Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: Potential role of histone deacetylase 6

Kim, In Ah; No, Mina; Lee, Jang Mi; Shin, Jin Hee; Oh, Jee Sun; Choi, Eun Jung; Kim, Il Han; Atadja, Peter; Bernhard, Eric J.

doi:10.1016/j.radonc.2009.03.008

Cited by 38 publications

(22 citation statements)

References 37 publications

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“…It is thus conceivable that LBH589 can control E-cadherin independently of estradiol and this is not affected by the level of expression of Snail, in agreement with recent observations in ovarian carcinoma (41). Snail requires histone deacetylase activity to repress E-cadherin promoter and it has already been demonstrated that treatment with trichostatin A is sufficient to block this effect (42). Our data suggest that LBH589 in MDA-MB-231 breast cancer acts directly on the CDH1 promoter and does not need to modify E-cadherin transcriptional repressors to induce E-cadherin expression and to modify the cell aggressive attitude.…”

Section: Discussionsupporting

confidence: 87%

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

Fortunati

Marano

Bandino

et al. 2013

International Journal of Oncology

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Abstract. Triple-negative breast cancer (TNBC) is a very aggressive type of tumour and its aggressiveness is linked to E-cadherin downregulation. In estrogen-sensitive breast cancer, high levels of E-cadherin fit with high levels of ERα and MTA3 (a component of the transcription Mi-2/NuRD complex with intrinsic DAC activity). In TNBC the E-cadherin downregulation could be due to epigenetic silencing of the CDH1 gene as well as to the lack of a fully functioning ERα-activated pathway. We report that the pan-histone deacetylase inhibitor LBH589, a potent anti-proliferative agent, induced E-cadherin expression on cell membranes of MDA-MB-231 cells (TNBC), determining a reduction of cell invasion and migration. Even though E-cadherin expression in breast cancer is also regulated by estradiol and the ERα/MTA3/Snail/Slug pathway, LBH589 is able to increase E-cadherin without affecting the estrogen pathway. In fact, no expression of ERα, PR and FoxA1 was observed in MDA-MB-231 cells before and after LBH589 treatment; furthermore, the drug caused an increase in Snail and Slug expression with a concomitant reduction of MTA3 levels. Taking into consideration its anti-proliferative and anti-invasive properties, we suggest the use of LBH589 in aggressive breast cancer refractory to hormonal therapy. IntroductionBreast cancer, the most common cancer in women all over the world (1), is generally managed with success thank to available treatments (2). Regrettably, resistance to conventional therapy and increasing in metastatic and aggressive disease are emerging problems (3,4). A particular aggressive subtype of breast cancer is the triple-negative breast cancer (TNBC) that is defined by the absence of ER, PR and Her2/neu (5,6). TNBC generally occurs more frequently in younger women, frequently presents early metastatic spread and has poor overall prognosis (7,8).In breast cancer, as well as in other tumour types, epigenetic modifications are considered a crucial mechanism involved in cancer growth, dedifferentiation and aggressiveness; indeed, epigenetic deregulation can alter a number of molecular pathways involved in the control of cell function. Epigenetic drugs, able to restore normal epigenome in cancer cells, are under extensive pharmacological research (9). In breast cancer, histone acetylation state is considered of great importance. Histone acetylation and deacetylation, controlled by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs), affect chromatin conformation and, therefore, gene transcription, DNA repair and replication, and cell cycle checkpoints (10). Altered expression of HDACs has been reported in breast cancer by several authors (11,12). Therefore, HDAC inhibitors (DCI) are considered valuable therapeutic tools and have been under extensive evaluation. DCI vorinostat (13), for example, in association with paclitaxel and bevacizumab induced a partial or complete response in >50% of patients with metastatic breast cancer. The antiproliferative and re-differentiating effect of sev...

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Section: Discussionsupporting

confidence: 87%

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

Fortunati

Marano

Bandino

et al. 2013

International Journal of Oncology

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“…and 200 nM LBH589 alone or in association with 4OHTamoxifene were effective in reducing the growth of ER-negative MDA-MB 231cells [25] and that LBH589 significantly reduced the viability of ER-positive MCF-7 cells [26] and increased the fraction of dying cells after radiation exposure [27]. Here we demonstrate that LBH589 alone, in nanomolar range which is far from toxic range in humans [28], is able to reduce the viability of ER-positive MCF-7…”

Section: Discussionmentioning

confidence: 58%

The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)

Fortunati

Catalano

Marano

et al. 2010

Breast Cancer Res Treat

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International audienceNew drugs with anti-tumor activity, also able to modify the expression of selected molecules, are under evaluation in breast cancer which is becoming resistant to conventional treatment, or in metastatic disease. The sodium-iodide symporter (NIS), which mediates iodide uptake into thyroid cells, and is the molecular basis of radioiodine imaging and therapy in thyroid cancer, is also expressed in a large portion of breast tumors. Since NIS expression in breast cancer is not sufficient for a significant iodide uptake, drugs able to induce its expression and correct function are under evaluation. In the present study, we report for the first time that the pan-deacetylase (DAC) inhibitor LBH589 (panobinostat) significantly induced NIS, both as mRNA and as protein, through the increase of NIS promoter activity, with the final consequence of obtaining a significant up-take of iodide in MCF7, T47D, and MDA-MB231 breast cancer cells. Moreover, we observed that LBH589 causes a significant reduction in cell viability of estrogen-sensitive and -insensitive breast cancer cells within nanomolar range. The anti-tumor effect of LBH589 is sustained by apoptosis induction and cell cycle arrest in G/M. In conclusion, our data suggest that LBH589 might be a powerful tool in the management of breast cancer due to its multiple effects and support a potential application of LBH589 in the diagnosis and treatment of this disease

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“…117 These effects extend to chromatin structure, as EGFR can be found in RIF, where it associates with histone acetyltransferase KAT5 (Tip60) to regulate ATM phosphorylation of TIF1-β with resultant heterochromatin relaxation. [118][119][120] One message from these studies is that cells can integrate cues from the microenvironment into DNA repair and chromatin dynamics to ultimately influence cell death and survival. This level of integration will probably also exist for other signalling pathways, which might expand the possibilities for targeted radiotherapeutic intervention.…”

Section: Growth Factors and Radiotherapymentioning

confidence: 99%

Opportunities and challenges of radiotherapy for treating cancer

2015

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The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

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Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER-2 signaling: Potential role of histone deacetylase 6

Cited by 38 publications

References 37 publications

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS)

Opportunities and challenges of radiotherapy for treating cancer

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