Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms

• Published in: Experimental hematology 2013-03, Vol.41 (3), p.261-270.e4
• Main Authors: Gao, Shen-meng, Chen, Chi-qi, Wang, Lu-yao, Hong, Li-li, Wu, Jian-bo, Dong, Pei-hong, Yu, Fu-jun
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Advanced Basic Science; Blotting, Western; Butyrates - pharmacology; Cell Line, Tumor; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Granulocyte-Macrophage Progenitor Cells - drug effects; Granulocyte-Macrophage Progenitor Cells - metabolism; Hematology, Oncology and Palliative Medicine; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; K562 Cells; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - pathology; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction - drug effects; STAT Transcription Factors - genetics; STAT Transcription Factors - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Up-Regulation - drug effects
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2012.10.012

Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia. Histone deacetylases (HDACs) inhibitors have been reported to possess anticancer activity through different mechanisms. However, whether HDACs inhibitors suppress JAK2/STAT signaling in MPNs is still unknown. In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3, both of which are the potent feedback inhibitors of JAK2/STAT signaling. SB upregulated the expression of SOCS1 and SOCS3 by triggering the promoter-associated histone acetylation of SOCS1 and SOCS3 in K562 and HEL cell lines. Importantly, we found that upon knockdown of each class I HDACs, only knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3. Moreover, overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling in K562 and HEL cells. Furthermore, SB increased the transcript levels of SOCS1 and SOCS3 and inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Taken together, these data establish a new anticancer mechanism that SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3. Thus, HDACs inhibitors may have therapeutic potential for the treatment of MPNs.