Biochemical and Biophysical Research Communications
The histone demethylase PHF8 promotes adult acute lymphoblastic leukemia through interaction with the MEK/ERK signaling pathway
Graphical abstract
Introduction
Acute lymphoblastic leukemia (ALL), a clonal hematological malignant disorder characterized by the expansion and accumulation of lymphoid progenitor cells in bone marrow and other tissues, affects both children and adults [1]. Compared with childhood ALL, the overall survival of which has improved to greater than 80% for 5 years with multi-agent treatment regimens, the average survival of adult patients between 18 and 60 years of age with ALL is only 35% [2]. ALL remains an important cause of morbidity due to hematological malignancies in adults, and the identification of novel pathogenic mechanisms and therapeutic targets is needed to improve its prognosis.
ALL is a heterogeneous disease comprising diverse subtypes resulting from multiple genetic alterations with varying responses to therapies [3]. In recent years, dysregulation of the human epigenome has emerged as a significant theme in the development of ALL [4]. Multiple recurrent somatic alterations in epigenetic genes, such as Dnmt3a [4], Tet1 [5], Ezh2 [6], and Hdac7 [7], are involved in ALL. Furthermore, Fbxl10 transgenic mice spontaneously develop B-lymphocytic leukemia [8]. The histone demethylase RBP2 promotes adult ALL by upregulating BCL2 [9]. MicroRNA 193b-3p acts as a tumor suppressor by targeting the Myb oncogene in T-cell ALL (T-ALL) [10]. However, most of the epigenetic mechanisms in ALL pathogenesis remain elusive.
PHD finger protein 8 (PHF8), a member of the Jumonji domain-containing (JmjC) histone demethylase family, contains a plant homeodomain (PHD) and a catalytic JmjC domain [11]. In recent years, various studies have shown that PHF8 is involved in the tumorigenesis and progression of multiple malignancies, such as non-small cell lung cancer [12], breast cancer [13] and prostate cancer [14], as a transcriptional regulator that influences the cell cycle [15], proliferation [14], apoptosis [12], and epithelial-to-mesenchymal transition (EMT) [16]. Furthermore, PHF8 regulates the response to retinoic acid in acute promyelocytic leukemia [17] and participates in the NOTCH1 multifunctional complex [18], but the specific role and mechanisms of PHF8 in ALL remain to be explored.
Novel therapeutic strategies have been used to modify the improperly activated cell signaling pathways responsible for cell proliferation and/or apoptosis of leukemic blasts [19]. The MEK/ERK pathway plays a central role in controlling diverse cellular processes that regulate cancer progression and participates in the pathogenesis of various malignancies, including ALL [20]. ERK1/2 phosphorylation acts as an independent predictor of prognosis in newly diagnosed adult ALL [19]. The anti-leukemic function of MEK inhibitors is being investigated in clinical trials [21]. In addition to activation by acquired mutations of upstream molecules, the MEK/ERK pathway is also regulated by epigenetic factors, such as the histone lysine methyltransferase SMYD3 [22]. Compared to genetic mutations, which are irreversible, epigenetic molecules involved in the regulation of the MEK/ERK pathway are more ideal therapeutic targets for adult ALL.
In this study, we report that the histone demethylase PHF8 acts as an oncogenic protein in adult ALL in vitro and in vivo. PHF8 expression is extensively upregulated in ALL samples and associated with ALL progression. PHF8 knockdown inhibits proliferation and promotes apoptosis of ALL cells in vitro and attenuates cell growth in vivo. Moreover, we elucidate a novel positive feedback loop between PHF8 and the MEK/ERK pathway. PHF8 may serve as a candidate epigenetic target for adult ALL alone or in combination with MEK/ERK pathway inhibitors.
Section snippets
Patient samples
A total of 65 bone marrow samples used in this study were obtained from the Department of Hematology of Qilu Hospital of Shandong University in China from 2012 to 2016. This study was approved by the Medical Ethics Committee of the Medical School at Shandong University. Informed consent was obtained from all patients.
Cell culture and reagents
The ALL cell lines Nalm-6 and Jurkat were obtained from American Type Culture Collection (ATCC) and cultured in RPMI 1640 medium (Life Technologies, Carlsbad, CA) supplemented with
PHF8 is upregulated in adult ALL and associated with ALL progression
To determine whether PHF8 participates in adult ALL, we first queried PHF8 expression in bioinformatics databases. We found that PHF8 was overexpressed in ALL bone marrow samples (n = 710) compared to non-leukemia or healthy bone marrow samples (n = 73) (P < .0001, Fig. 1A) (GEO, GSE13159). Although PHF8 expression was upregulated in both T-ALL (P < .0001, n = 170) and B-cell ALL (B-ALL, P < .0001, n = 540), the level of PHF8 was much higher in B-ALL than that in T-ALL (P < .0001, Fig. 1B).
To
Discussion
Histone methylation is an important epigenetic mark that regulates gene expression [23]. Deregulation of histone-modifying enzymes is involved in the development and progression of ALL. For instance, the histone demethylase KDM5B is overexpressed in B-ALL and is believed to be a novel therapeutic target [24]. Inhibition of the histone demethylase UTX acts as a selective epigenetic therapy against TAL1-driven T-ALL [25]. PHF8 has been reported to be a member of the Notch activation complex in
Disclosure of conflict of interest
None.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (grant numbers 81670146, 81470318, 81170514), the Cross Training Program of Shandong University (grant number 2015JC052), the key research and development project of Shandong province (grant number 2017GSF18109) and the project of Shandong province science and technology development plans (grant number 2014GSF118114).
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