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Inhibition of Phospholipase D2 Augments Histone Deacetylase

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Inhibition of Phospholipase D2 Augments Histone Deacetylase Hwang et al. Biol Res (2020) 53:34 https://doi.org/10.1186/s40659-020-00294-3 Biological Research RESEARCH ARTICLE Open Access Inhibition of phospholipase D2 augments histone deacetylase inhibitor-induced cell death in breast cancer cells Won Chan Hwang1,2†, Dong Woo Kang1†, Youra Kang3, Younghoon Jang4, Jung‑Ae Kim3 and Do Sik Min2* Abstract Background: Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their efect on tumor treat‑ ment has been disappointing mainly due to the acquisition of HDAC inhibitor resistance. However, the mechanisms underlying such resistance remain unclear. Methods: In this study, we performed Western blot, q‑PCR, and promoter assay to examine the expression of HDAC inhibitor‑induced phospholipase D2 (PLD2) in MDA‑MB231and MDA‑MB435 breast cancer cells. Apoptosis and proliferation were analyzed by fow cytometry. In addition to invasion and migration assay, angiogenesis was further measured using in vitro tube formation and chick embryo chorioallantoic membrane model. Results: HDAC inhibitors including suberoylanilide hydroxamic acid (SAHA), trichostatin, and apicidin, induce expres‑ sion of PLD2 in a transcriptional level. SAHA upregulates expression of PLD2 via protein kinase C‑ζ in breast cancer cells and increases the enzymatic activity of PLD. The combination treatment of SAHA with PLD2 inhibitor signifcantly enhances cell death in breast cancer cells. Phosphatidic acid, a product of PLD activity, prevented apoptosis promoted by cotreatment with SAHA and PLD2 inhibitor, suggesting that SAHA‑induced PLD2 expression and subsequent acti‑ vation of PLD2 might confers resistance of breast cancer cells to HDAC inhibitor. The combinational treatment of the drugs signifcantly suppressed invasion, migration, and angiogenesis, compared with that of either treatment. Conclusion: These fndings provide further insight into elucidating the advantages of combination therapy with HDAC and PLD2 inhibitors over single‑agent strategies for the treatment of cancer. Keywords: Phospholipase D2, Histone deacetylase inhibitor, Apoptosis, Angiogenesis, Chemoresistance Background activity of HDAC, leading to unrestricted histone acetyl- Resistance of cancers to various chemotherapeutic transferase (HAT) activity and increase gene expres- treatment, is a major obstacle in oncology [1, 2]. Since sion. Several HDAC inhibitors are in clinical trials both epigenetic alterations are associated with therapeu- in monotherapy and in combination therapy. Most of tic resistance and reversible, they are considered as a the responses using HDAC inhibitors as a monotherapy promising target for therapeutic intervention. Histone were observed in hematological cancers with only a few deacetylase (HDAC) inhibitors suppress the deacetylase observed in solid tumors. HDAC inhibitors induce cell cycle arrest, activation of apoptotic pathways, induc- tion of autophagy and reactive oxygen species gen- *Correspondence: [email protected] †Won Chan Hwang and Dong Woo Kang contributed equally to this work eration [3–6]. However, HDAC inhibitors also show 2 College of Pharmacy, Yonsei University, 85 Songdogwahak‑ro, therapeutic resistance via epigenetic alternations, drug Yeonsu‑gu, Incheon 21983, South Korea efux and pro-survival mechanisms [7–12]. Tus, modu- Full list of author information is available at the end of the article lation of target genes responsible for resistance to HDAC © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea‑ tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo‑ main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hwang et al. Biol Res (2020) 53:34 Page 2 of 11 inhibitors can be used for strategies to maximize the ef- time- and dose-dependent manners along with increas- cacy of HDAC inhibitors. ing the accumulation of acetylated histone 4 in MDA-MB Phospholipase D (PLD) hydrolyzes phospholipid to 231 cells (Fig. 1c). All of the tested HDAC inhibitors pro- generate phosphatidic acid (PA), which consequently duced signifcant increases in promoter activity of PLD2 activates a signaling cascade for cell growth and sur- in the MDA-MB231 and MDA-MB435 cells (Fig. 1d). vival [13–15]. Elevated expression and activity of PLD Tese results indicate that PLD2 is upregulated by HDAC have been found in many types of human cancer, includ- inhibitors in a transcriptional level. ing breast [16], colon [17], and gastric [18]. Microar- ray data showed that level of PLD1 was upregulated in PKCζ is required for SAHA‑induced PLD2 expression HDAC inhibitor-treated cancer cells [19]. In particular, To investigate whether the certain signaling molecules the expression level of PLD2 has been correlated with are required for SAHA-induced PLD2 upregulation, the survival of patients with colorectal carcinoma [20]. PLD2 promoter activity were measured in MDA-MB231 Moreover, PLD2 point mutations have been detected cells that had been pretreated with various inhibitors in patients with breast cancer [21], and cell invasion of prior to incubation with SAHA. SAHA-induced PLD2 highly metastatic cancer cells is dependent on PLD2 expression was largely abolished upon blockade of the [22]. Tese reports suggest that upregulation of PLD2 is activity of the atypical protein kinase C (PKC), PKCζ, by involved in oncogenic signaling and tumorigenesis. In PS-PKCζ (Fig. 2a). Rottlerin (a PKCδ inhibitor), AG1487 the present study, we show that expression of PLD2 is (a EGFR tyrosine kinase inhibitor), PDTC (an NF KB upregulated by HDAC inhibitors, and confers resistance inhibitor), rapamycin (an mTOR inhibitor), B581 (a Ras to HDAC inhibitors in breast cancer cells. Combination farnesylation inhibitor), Bay117085 (an IκBα phospho- therapy with SAHA and PLD2 inhibitor signifcantly sup- rylation inhibitor), U0126 (a MEK inhibitor), SP600125 pressed cell proliferation and angiogenesis and enhanced (a JNK inhibitor), SB203580 (a p38 MAPK inhibitor), apoptosis of breast cancer cells, suggesting that com- LY294002 (a PI3K inhibitor), PP2 (an Src inhibitor), and bined treatment with these drugs might ofer a promising MTM (an Sp1 inhibitor) had no efect on SAHA-induced therapeutic approach to the treatment of cancer by over- PLD2 promoter activity (Fig. 2a). As positive controls, coming resistance to HDAC inhibitors. efcacy of these inhibitors was confrmed (Additional fle 1: Figure S1a, b). Results Te critical participation of PKCζ in SAHA-induced HDAC inhibitors upregulate expression of PLD2 PLD2 upregulation was confrmed by reporter gene assay We investigated whether HDAC inhibitors afect the and immunoblot analysis (Fig. 2b), which revealed that expression of PLD2. HDAC inhibitors such as trichosta- dominant-negative (DN) PKCζ, a kinase-inactive mutant tin (TSA), suberoylanilide hydroxamic acid (SAHA, also form of PKCζ, abrogated SAHA-induced PLD2 expres- known as Vorinostat), and apicidin upregulated expres- sion. Te role of PKCζ was further investigated by the sions of PLD2 in MDA-MB 231 and MDA-MB435 breast siRNA analysis in which SAHA-induced PLD2 expres- cancer cells as determined by q-PCR (Fig. 1a). A subtype sion was signifcantly reduced by knockdown of PKCζ of breast cancer is basal-like breast cancer, also known (Fig. 2c). Moreover, SAHA stimulated PKCζ as indicated as triple-negative breast cancer. Given its lack of estro- by the phosphorylation of PKCζ at Tr 410 (Fig. 2d), gen receptor, progesterone receptor, and low expres- which is critical for PKCζ activity [24]. Collectively, these sion of human epidermal growth factor receptor, there results demonstrate that PKC-ζ is critical for SAHA- is no efective biological targeted therapy. MDA-MB231 induced PLD2 expression. and MDA-MB435 are known as triple-negative human breast cancer cells, which have highly aggressive behav- PLD2 inhibition accelerates SAHA‑induced suppression iors as they go through reattachment, cell metastasis, and of cell proliferation cell aggregation. Tere is a need for an efective therapy Next, we investigated whether SAHA afects cell viabil- that treats triple-negative breast cancer. Moreover, the ity. SAHA doses below 2 μM did not afect the viability HDAC inhibitors upregulated the expression of PLD2 of MDA-MB231 cell, but SAHA above 5 μM decreased protein and increased the level of acetylated histone 4 in signifcantly the cell viability (Fig. 3a). Elevated expres- the cells, as determined by western blot assay using the sion and activity of PLD are known to be involved in antibody to PLD2 (Fig. 1a). Moreover, treatment with the increased proliferation of cancer cells. Tus, we exam- HDAC inhibitors stimulated PLD activity in the MDA- ined whether SAHA-induced
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