Coupling HDAC4 with transcriptional factor MEF2D abrogates SPRY4-mediated suppression of ERK activation and elicits hepatocellular carcinoma drug resistance

被引：16

作者：

Ma, Qingxia ^{[1
,2
,3
]}

Xu, Qianqian ^{[1
,2
,4
]}

Zhao, Jiaojiao ^{[1
,2
,3
]}

Zhang, Wenwei ^{[5
]}

Wang, Qiang ^{[6
]}

Fang, Jing ^{[1
,2
]}

Lu, Zhimin ^{[7
]}

Liu, Jia ^{[4
]}

Ma, Leina ^{[1
,2
]}

机构：

[1] Qingdao Univ, Inst Canc, Affiliated Hosp, 1 Ningde Rd, Qingdao 266071, Peoples R China

[2] Qingdao Canc Inst, 1 Ningde Rd, Qingdao 266071, Peoples R China

[3] Qingdao Univ, Sch Basic Med, 1 Ningde Rd, Qingdao 266071, Peoples R China

[4] Qingdao Univ, Sch Pharm, Dept Pharmacol, 1 Ningde Rd, Qingdao 266071, Peoples R China

[5] EASCO European Assoc Sci Career Orientat, 42 Ave Pasteur, F-91550 Paray Vieille Poste, France

[6] Shandong Second Prov Gen Hosp, Dept Oncol, Jinan 250021, Peoples R China

[7] Zhejiang Univ, Zhejiang Prov Key Lab Pancreat Dis, Affiliated Hosp 1, Inst Translat Med,Sch Med, 268 Kaixuan Rd, Hangzhou 310012, Peoples R China

来源：

CANCER LETTERS | 2021年 / 520卷

关键词：

HDAC4; MEF2D; SPRY4; ERK; Sorafenib; HCC; SORAFENIB RESISTANCE; DOWN-REGULATION; CELLS; OVEREXPRESSION; PROLIFERATION; CONTRIBUTES; PROGRESSION; OVARIAN; GROWTH; METASTASIS;

D O I：

10.1016/j.canlet.2021.07.049

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Hepatocellular carcinoma (HCC) lacks effective treatment, and the patients rapidly develop the acquired resistance to sorafenib with less defined mechanisms. Here, we demonstrate that transcriptional factor myocyte enhancer factor 2D (MEF2D) overexpression is detected in sorafenib-resistant HCC specimens and HCC cell lines and predicts poor prognosis of sorafenib-treated HCC patients. Mechanistically, MEF2D in complex with histone deacetylase HDAC4 directly binds to the SPRY4 promoter regions and suppresses the transcriptional expression of SPRY4, which is a negative regulator of MAPK/ERK signaling pathway. Inhibition of HDAC4 with its clinically used inhibitor induces SPRY4 expression and inhibition of ERK activity, resulting in sensitization of HCC cells to sorafenib-induced apoptosis and greatly improved inhibition of liver tumor growth in mice with sorafenib treatment. These findings highlight the critical role of coupling HDAC4 with MEF2D in activation of ERK by suppressing SPRY4 and underscore the great potential to improve HCC treatment by combined administration of sorafenib with HDAC4 inhibitors.

引用

页码：243 / 254

页数：12