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

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

  • Cancer Lett. 2021 Nov 1;520:243-254. doi: 10.1016/j.canlet.2021.07.049.
Qingxia Ma 1,  Qianqian Xu 2,  Jiaojiao Zhao 1,  Wenwei Zhang 3,  Qiang Wang 4,  Jing Fang 5,  Zhimin Lu 6,  Jia Liu 7,  Leina Ma 8
Affiliations

Affiliations

  • 1 Cancer Institute, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 1 Ningde Road, Qingdao, 266071, China; School of Basic Medicine, Qingdao University, 1 Ningde Road, Qingdao, 266071, China.
  • 2 Cancer Institute, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 1 Ningde Road, Qingdao, 266071, China; Department of Pharmacology, School of Pharmacy, Qingdao University, 1 Ningde Road, Qingdao, 266071, China.
  • 3 E.A.S.C.O. European Association of Scientific Career Orientation, 42 Avenue Pasteur, 91550, Paray-Vieille Poste, France.
  • 4 Oncology Department, Shandong Second Provincial General Hospital, Jinan, 250021, China.
  • 5 Cancer Institute, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 1 Ningde Road, Qingdao, 266071, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease of the First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, 268 Kaixuan Road, Hangzhou, 310012, China.
  • 7 Department of Pharmacology, School of Pharmacy, Qingdao University, 1 Ningde Road, Qingdao, 266071, China. Electronic address: [email protected].
  • 8 Cancer Institute, The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, 1 Ningde Road, Qingdao, 266071, China. Electronic address: [email protected].
PMID: 34339801 DOI: 10.1016/j.canlet.2021.07.049
Abstract

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.

Keywords

ERK; HCC; HDAC4; MEF2D; SPRY4; Sorafenib.

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