A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells
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Guanhua Song1, Lulu Shi1, Yuqi Guo1, Linchang Yu1, Lin Wang2, Xiaoyu Zhang1, Lianlian Li1, Yang Han1, Xia Ren1, Qiang Guo1, Kehong Bi3, Guosheng Jiang1
1Department of Hemato-Oncology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Key Medical Laboratory for Tumor Immunology and Traditional Chinese Medicine Immunology of Shandong, Jinan, Shandong, China
2Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan, Shandong, China
3Qianfoshan Hospital of Shandong, Jinan, Shandong, China
Kehong Bi, e-mail: email@example.com
Guosheng Jiang, e-mail: firstname.lastname@example.org
Keywords: PADI4, methylation, differentiation, leukemia
Received: April 24, 2015 Accepted: November 20, 2015 Published: December 10, 2015
All-trans retinoic acid (ATRA) treatment yields cure rates > 80% through proteasomal degradation of the PML-RARα fusion protein that typically promotes acute promyelocytic leukemia (APL). However, recent evidence indicates that ATRA can also promote differentiation of leukemia cells that are PML-RARα negative, such as HL-60 cells. Here, gene expression profiling of HL-60 cells was used to investigate the alternative mechanism of impaired differentiation in APL. The expression of peptidylarginine deiminase 4 (PADI4), encoding PAD4, a protein that post-translationally converts arginine into citrulline, was restored during ATRA-induced differentiation. We further identified that hypermethylation in the PADI4 promoter was associated with its transcriptional repression in HL-60 and NB4 (PML-RARα positive) cells. Functionally, PAD4 translocated into the nucleus upon ATRA exposure and promoted ATRA-mediated differentiation. Mechanistic studies using RNAi knockdown or electroporation-mediated delivery of PADI4, along with chromatin immunoprecipitation, helped identify PU.1 as an indirect target and SOX4 as a direct target of PAD4 regulation. Indeed, PAD4 regulates SOX4-mediated PU.1 expression, and thereby the differentiation process, in a SOX4-dependent manner. Taken together, our results highlight an association between PAD4 and DNA hypermethylation in APL and demonstrate that targeting PAD4 or regulating its downstream effectors may be a promising strategy to control differentiation in the clinic.
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