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(Hdacs) Guided Novel Therapies for T-Cell Lymphomas Qing Zhang1, Shaobin Wang2, Junhui Chen1, Zhendong Yu3

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(Hdacs) Guided Novel Therapies for T-Cell Lymphomas Qing Zhang1, Shaobin Wang2, Junhui Chen1, Zhendong Yu3 Int. J. Med. Sci. 2019, Vol. 16 424 Ivyspring International Publisher International Journal of Medical Sciences 2019; 16(3): 424-442. doi: 10.7150/ijms.30154 Review Histone Deacetylases (HDACs) Guided Novel Therapies for T-cell lymphomas Qing Zhang1, Shaobin Wang2, Junhui Chen1, Zhendong Yu3 1. Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China. 2. Health Management Center of Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China. 3. China Central Laboratory of Peking University Shenzhen Hospital, Shenzhen, Guangdong, 518036, China. Corresponding authors: Dr. Qing Zhang, email: [email protected]; Dr. Zhendong Yu, email: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.09.24; Accepted: 2018.12.19; Published: 2019.01.29 Abstract T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas. Key words: Histone deacetylases (HDACs), T-cell lymphomas, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, combination therapy 1. Introduction patients with T-cell lymphomas usually have a poor 1.1 T-cell lymphomas prognosis and easy to relapse. T-cell lymphomas encompass a heterogeneous group of malignancies comprising 15-20% of systemic 1.2 Current therapeutic strategies for T-cell lymphomas and less than 10% non-Hodgkin lymphomas lymphomas. T-cell malignancies are endemic in East Currently, chemotherapy is the most preferred Asia, the Caribbean, intertropical Africa, the Middle treatment in patients with T-cell lymphoma. With the East, South America, and Papua New Guinea. Adult development of intensified chemotherapy, the T-cell lymphoma caused by human T-cell leukemia prognosis of T-cell leukemia/lymphoma has virus-1 is one of the most popular T-cell malignancies. gradually improved. However, due to the Up to now, there are about 5-20 million patients non-specific toxicity of current chemotherapeutic infected with HTLV-1 around world. According to compounds to normal cells, the progressive loss of WHO/EORTC classification based on the clinical quality of life is a matter of concern [2]. Besides, pathology indications, T-cell malignancies are divided patients with relapse and resistance to conventional into extra nodal T cell lymphoma, cutaneous T cell chemotherapy exhibit limited efficacy in the salvage lymphomas (Sézary syndrome and Mycosis setting. fungoides), anaplastic large cell lymphoma, and Recently, the booming targeted therapeutic angioimmunoblastic T cell lymphoma [1]. The clinical strategies have become the forefront therapeutics in performance and pathogenesis are divergent between patients with severe lymphomas and achieved different T-cell lymphomas; the therapeutic strategies promising therapeutic effects, such as immune are different but with some overlap especially in their therapies of antibodies against CTLA 4 and PD 1 early stage. However, because of the comprehensive /PDL 1 [3], B cell receptor signaling pathway pathogenesis and limited therapeutic strategies, inhibitors (e.g., ibrutinib [4]), NK cells (e.g., AFM13 http://www.medsci.org Int. J. Med. Sci. 2019, Vol. 16 425 [5]), bispecific T engager (BiTE, blinatumomab [6]), T T-cell malignancies have been investigated under the cell receptor (e.g., CART19 [7, 8]). However, all these intervention of HDAC inhibitors (Figure 1), but still gorgeous strategies mentioned above have not been not been fully elucidated. testified or not suitable in the treatment of T-cell lymphomas. Table 1. Classification of histone deacetylases (HDACs) The treatment of patients with T-cell lymphomas Cofactor Class HDAC Localization is challenging. Novel therapeutic strategies are members urgently warranted to improve the therapeutic effects Zn2+--dependent Class I HDAC 1,2,3,8 Nucleus (HDAC 8, partially in the of T-cell lymphomas. Thus new flourishing cytoplasm) Class HDAC 4,5,7,9 Nucleus/cytoplasm therapeutic targets and techniques (drugs, techniques IIA or combinational trials) would provide opportunities Class HDAC 6,10 Mainly in the cytoplasm IIB for the treatment of patients with T-cell malignancies. Class HDAC 11 Nucleus/cytoplasm HDACs, kinases, T/B cell receptors, checkpoints or IV NAD+--dependent Class SIRT 1,6,7 Nucleus other related key modulators are promising choices. III SIRT 2 Cytoplasm In this review, we will focus on the role of HDACs in SIRT 3,4,5 Mitochondria T-cell lymphomas and the potential applications as therapeutic targets for the treatment of patients with 2.2.1 Epigenetic modulation T-cell malignancies. Except for genetic mutation, chromatin 2. Histone deacetylases (HDACs) differentiation, the reversible epigenetic alterations are the main alterations for cancer initiation, 2.1 Brief profile of HDACs progression and invasion [20]. HDACs interfere with Histone deacetylases are a class of enzymes epigenetic chromatin modification by de-acetylating deacetylating the acetyl group from ε-N-acetyl lysine histones and non-histone proteins of nuclear amino acid from a histone, which lead to the tight transcription factors mediating carcinogenesis [21]. wrapping of DNA. HDACs play a key role in the Besides, HDACs participate in the mediation of homeostasis maintenances of histone acetylation oncogenes of Bcl-xL-[22], Bcl2-[23], or TCRβ [22], euchromatin and heterochromatin in living system [9, c-Myc [24], Notch3 [25]. 10]. There are 18 HDACs recognized up to now, 2.2.2 Cytokines regulation divided into HDAC I (HDAC 1, 2, and 3: mainly in the nucleus; HDAC 8: partially in the cytoplasm), HDAC Cytokines are the important participators in II (HDAC 4, 5, 6, 7, 9, and 10: shuttling in and out of immune regulation. A response rate of 30% for the nucleus), as Table 1 showed [11]. Considering the cutaneous T-cell lymphoma (CTCL) expressing high main function of the process of de-acetylation, affinity IL-2 receptor (IL-2R) was demonstrated in HDACs act as key epigenetic modulators of essential Phases I and II clinical trials of DAB (389) IL-2 by biological processes by modifying histones of inhibition of histone deacetylases (HDACs) chromatin or non-histone proteins (PTEN, interfering with 0.06 mM arginine butyrate[26]. APE1/Ref-1 (APEX1), NF-κB, aggressomes, et al.) Up-regulation of HDAC1 and HDAC6 and [12]. Besides, HDACs are involved in protein transcriptional induction of the conco-miR-21 were degradation, especially HDAC6 that was reported to found in CTCL, which was caused by excessive interfere with HSP90 via degrading HSP90-interacting autocrine secretion of IL-15 in T-cells. IL-15 mediated proteins [13, 14]. HDACs are thought to be the main inflammation was critical in CTCL, and a novel pathogenic factors to both leukemia and other solid oncogenic regulatory loop between IL-15, HDAC 1/6, tumors, such as chronic myeloid leukemia, chronic and miR-21 was discovered [27]. Besides, HDAC lymphocytic leukemia[15], pediatric acute myeloid deactivation and concomitant down regulation of leukemia, acute promyelocytic leukemia, renal cancer, CD27 were found in TEL-AML positive leukemia by colorectal and gastric cancer, breast tumors and so CD40 ligation [28]. Under the improvement of on[16]. In this review, we have focused on the role of immune surveillance by CD40 ligation in patients HDACs in T-cell lymphomas and the application of with TEL-AML, a potential increased relapse-free HDAC inhibitors as T-cell lymphomas treatments. survival was observed with the presence of other risks. 2.2 Modes of action in T-cell lymphoma 2.2.3 Apoptosis The elaboration of HDACs in the pathogenesis, therapy and prognosis of T-cell lymphomas would HDACs mediated the pro-apoptotic response in help a lot in the treatment of patients with T-cell a decreased way and increased the apoptotic lymphomas. The precise mechanisms of HDACs in threshold in various hematological and solid http://www.medsci.org Int. J. Med. Sci. 2019, Vol. 16 426 Figure 1. Molecular functions of HDACs. This figure was adapted from Bodiford & Reddy (2014)[17], Hood & Shah (2016)[18], and Weiguo Zhu (2014)[19]. lymphomas. The inhibition of HDAC 1/2 was found correlation with an anti-apoptotic drug resistance to have a synergism effect with BCL11B (a key T-cell related molecule surviving [34], which was development regulator) in the anti-apoptosis effect in demonstrated by HDAC inhibitor SAHA in the CTCL lines [29]. HDACs promoted the acetylation of treatment of ATL cells. Considering the important the chaperone heat shock protein 90 (HSP90), leading regulation of HDAC in the downstream signal to the binding and stabilization of HSP90 client pathway and apoptotic related proteins, HDACs may proteins RASGRP1 and CRAF which activate the serve as potential drug target for T-cell malignancies mitogen-activated protein kinase pathway signaling in an apoptosis induction way. and down-regulate the pro-apoptotic BCL2 family member BIM both in vitro and in vivo. siRNA of 2.2.4 Autophagy RASGRP1, HSP90 inhibition or HDAC inhibition may Autophagy is a key self-salvage process to contribute to the cytotoxicity and apoptosis induction various stresses by degrading long-lived proteins and in lymphoid malignancies by influencing the signal damaged organelles. Except for the main function on pathway related to HSP90, RASGRP1, CRAF, and lysine de-acetylation in chromatin, HDACs also have BIM [30].
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