Full Text:   <2225>

Summary:  <1495>

CLC number: R392.11

On-line Access: 2019-01-07

Received: 2018-04-07

Revision Accepted: 2018-07-08

Crosschecked: 2019-01-02

Cited: 0

Clicked: 4735

Citations:  Bibtex RefMan EndNote GB/T7714


Wen-bo Ren


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2019 Vol.20 No.1 P.39-48


Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells

Author(s):  Wen-bo Ren, Xiao-jing Xia, Jing Huang, Wen-fei Guo, Yan-yi Che, Ting-hao Huang, Lian-cheng Lei

Affiliation(s):  College of Veterinary Medicine, Jilin University, Changchun 130062, China; more

Corresponding email(s):   leilc@jlu.edu.cn, leiliancheng@163.com

Key Words:  Interferon-γ, (IFN-γ, ), Cellular-abelsongene (c-Abl), Histone deacetylase 2 (HDAC2), Malignant cell growth

Wen-bo Ren, Xiao-jing Xia, Jing Huang, Wen-fei Guo, Yan-yi Che, Ting-hao Huang, Lian-cheng Lei. Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells[J]. Journal of Zhejiang University Science B, 2019, 20(1): 39-48.

@article{title="Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells",
author="Wen-bo Ren, Xiao-jing Xia, Jing Huang, Wen-fei Guo, Yan-yi Che, Ting-hao Huang, Lian-cheng Lei",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells
%A Wen-bo Ren
%A Xiao-jing Xia
%A Jing Huang
%A Wen-fei Guo
%A Yan-yi Che
%A Ting-hao Huang
%A Lian-cheng Lei
%J Journal of Zhejiang University SCIENCE B
%V 20
%N 1
%P 39-48
%@ 1673-1581
%D 2019
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1800211

T1 - Interferon-γ regulates cell malignant growth via the c-Abl/HDAC2 signaling pathway in mammary epithelial cells
A1 - Wen-bo Ren
A1 - Xiao-jing Xia
A1 - Jing Huang
A1 - Wen-fei Guo
A1 - Yan-yi Che
A1 - Ting-hao Huang
A1 - Lian-cheng Lei
J0 - Journal of Zhejiang University Science B
VL - 20
IS - 1
SP - 39
EP - 48
%@ 1673-1581
Y1 - 2019
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1800211

interferon-γ; (IFN-γ;) has been used to control cancers in clinical treatment. However, an increasing number of reports have suggested that in some cases effectiveness declines after a long treatment period, the reason being unclear. We have reported previously that long-term IFN-γ treatment induces malignant transformation of healthy lactating bovine mammary epithelial cells (BMECs) in vitro. In this study, we investigated the mechanisms underlying the malignant proliferation of BMECs under IFN-γ treatment. The primary BMECs used in this study were stimulated by IFN-γ (10 ng/mL) for a long term to promote malignancy. We observed that IFN-γ could promote malignant cell proliferation, increase the expression of cyclin D1/cyclin-dependent kinase 4 (CDK4), decrease the expression of p21, and upregulate the expression of cellular-abelsongene (c-Abl) and histone deacetylase 2 (HDAC2). The HDAC2 inhibitor, valproate (VPA) and the c-Abl inhibitor, imatinib, lowered the expression level of cyclin D1/CDK4, and increased the expression level of p21, leading to an inhibitory effect on IFN-γ-induced malignant cell growth. When c-Abl was downregulated, the HDAC2 level was also decreased by promoted proteasome degradation. These data suggest that IFN-γ promotes the growth of malignant BMECs through the c-Abl/HDAC2 signaling pathway. Our findings suggest that long-term application of IFN-γ may be closely associated with the promotion of cell growth and even the carcinogenesis of breast cancer.


方法:通过MTT实验检测IFN-γ长期刺激下细胞的增殖能力;蛋白质印迹(Western blot)检测cyclin D1/CDK4、p21、HDAC2、c-Abl蛋白的表达;免疫荧光观察c-Abl入核.


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Allington TM, Galliher-Beckley AJ, Schiemann WP, 2009. Activated Abl kinase inhibits oncogenic transforming growth factor-β signaling and tumorigenesis in mammary tumors. Faseb J, 23(12):4231-4243.

[2]Barneda-Zahonero B, Parra M, 2012. Histone deacetylases and cancer. Mol Oncol, 6(6):579-589.

[3]Bougarn S, Cunha P, Gilbert FB, et al., 2011. Technical note: validation of candidate reference genes for normalization of quantitative PCR in bovine mammary epithelial cells responding to inflammatory stimuli. J Dairy Sci, 94(5):2425-2430.

[4]Bradley WD, Koleske AJ, 2009. Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts. J Cell Sci, 122(19):3441-3454.

[5]Brightbill H, Schlissel MS, 2009. The effects of c-Abl mutation on developing B cell differentiation and survival. Int Immunol, 21(5):575-585.

[6]Carpi A, Nicolini A, Antonelli A, et al., 2009. Cytokines in the management of high risk or advanced breast cancer: an update and expectation. Curr Cancer Drug Tar, 9(8):9888-9903.

[7]Creagan ET, Schaid DJ, Ahmann DL, et al., 1990. Disseminated malignant melanoma and recombinant interferon: analysis of seven consecutive phase II investigations. J Invest Dermatol, 95(S6):S188-S192.

[8]Gonzalez-Zuñiga M, Contreras PS, Estrada LD, et al., 2014. c-Abl stabilizes HDAC2 levels by tyrosine phosphorylation repressing neuronal gene expression in Alzheimer’s disease. Mol Cell, 56(1):163-173.

[9]Hildmann C, Riester D, Schwienhorst A, 2007. Histone deacetylases—an important class of cellular regulators with a variety of functions. Appl Microbiol Biotechnol, 75(3):487-497.

[10]Horikoshi T, Fukuzawa KF, Hanada N, et al., 1995. In vitro comparative study of the antitumor effects of human interferon-α, β and γ on the growth and invasive potential of human melanoma cells. J Dermatol, 22(9):631-636.

[11]Kaplan DH, Shankaran V, Dighe AS, et al., 1998. Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA, 95(13):7556-7561.

[12]Krämer OH, 2009. HDAC2: a critical factor in health and disease. Trends Pharmacol Sci, 30(12):647-655.

[13]Krämer OH, Zhu P, Ostendorff HP, et al., 2003. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J, 22(13):3411-3420.

[14]Matsuzaki J, Tsuji T, Luescher IF, et al., 2015. Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses. Sci Rep, 5:14896.

[15]Mojic M, Takeda K, Hayakawa Y, 2018. The dark side of IFN-γ: its role in promoting cancer immunoeevasion. Int J Mol Sci, 19(1):89.

[16]Montgomery RL, Davis CA, Potthoff MJ, et al., 2007. Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Gene Dev, 21(14):1790-1802.

[17]Müller BM, Jana L, Kasajima A, et al., 2013. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer-overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer, 13:215.

[18]Muss HB, Caponera M, Zekan PJ, et al., 1986. Recombinant gamma interferon in advanced breast cancer: a phase II trial. Invest New Drugs, 4(4):377-381.

[19]Nam SW, Park JY, Ramasamy A, et al., 2005. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology, 42(4):809-818.

[20]Noh JH, Jung KH, Kim JK, et al., 2011. Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins. PLoS ONE, 6(11):e28103.

[21]Ren WB, Li Y, Xia XJ, et al., 2018. Arginine inhibits the malignant transformation induced by interferon-gamma through the NF-κB-GCN2/ eIF2α signaling pathway in mammary epithelial cells in vitro and in vivo. Exp Cell Res, 368(2):236-247.

[22]Sarhan D, D'Arcy P, Wennerberg E, et al., 2013. Activated monocytes augment TRAIL-mediated cytotoxicity by human NK cells through release of IFN-γ. Euro J Immunol, 43(1):249-257.

[23]Schiller JH, Pugh M, Kirkwood JM, et al., 1996. Eastern cooperative group trial of interferon gamma in metastatic melanoma: an innovative study design. Clin Cancer Res, 2(1):29-36.

[24]Trivedi CM, Zhu WT, Wang QH, et al., 2010. Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac Myocyte proliferation. Dev Cell, 19(3):450-459.

[25]Wang JYJ, 2014. The capable ABL: what is its biological function? Mol Cell Biol, 34(7):1188-1197.

[26]Weichert W, Röske A, Gekeler V, et al., 2008. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer, 98(3):604-610.

[27]Xia XJ, Che YY, Gao YY, et al., 2016a. Arginine supplementation recovered the IFN-γ-mediated decrease in milk protein and fat synthesis by inhibiting the GCN2/eIF2α pathway, which induces autophagy in primary bovine mammary epithelial cells. Mol Cell, 39(5):410-417.

[28]Xia XJ, Gao YY, Zhang J, et al., 2016b. Autophagy mediated by arginine depletion activation of the nutrient sensor GCN2 contributes to interferon-γ-induced malignant transformation of primary bovine mammary epithelial cells. Cell Death Discov, 2:15065.

[29]Xia XJ, Che YY, Zhang J, et al., 2016c. Diet-driven interferon-γ enhances malignant transformation of primary bovine mammary epithelial cells through nutrient sensor GCN2-activated autophagy. Cell Death Dis, 7(3):e2138.

[30]Yamaguchi T, Cubizolles F, Zhang Y, et al., 2010. Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev, 24(5):455-469.

[31]Zaidi MR, Merlino G, 2011. The two faces of interferon-γ in cancer. Clin Cancer Res, 17(19):6118-6124.

[32]Zhao HJ, Ho PC, Lo YH, et al., 2012. Interaction of proliferation cell nuclear antigen (PCNA) with c-Abl in cell proliferation and response to DNA damages in breast cancer. PLoS ONE, 7(1):e29416.

[33]Zhao HJ, Chen MS, Lo YH, et al., 2013. The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene, 33(11):1429-1437.

[34]Zhou HY, Cai Y, Liu DN, et al., 2018. Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21Waf1/Cip1 and p19INK4d upregulation in hepatocellular carcinoma. Cell Proliferat, 51(3):e12447.

[35]Zhu JF, Yamane H, Paul WE, 2010. Differentiation of effector CD4 T cell populations. Annu Rev Immunol, 28:445-489.

[36]Zuo H, Tell GS, Vollset SE, et al., 2014. Interferon-γ-induced inflammatory markers and the risk of cancer: the hordaland health study. Cancer, 120(21):3370-3377.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE