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  3. EZH2 suppresses insulinoma development by epigenetically reducing KIF4A expression via H3K27me3 modification

EZH2 suppresses insulinoma development by epigenetically reducing KIF4A expression via H3K27me3 modification

  • Gene. 2022 May 15;822:146317. doi: 10.1016/j.gene.2022.146317.
Suzhen Zhang 1,  Jun Liu 2,  Feng Li 3,  Mudan Yang 4,  Junping Wang 5
Affiliations

Affiliations

  • 1 Graduate School of Shanxi Medical University, Taiyuan 030013, Shanxi, PR China; The Second Department of Gastroenterology, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, Shanxi, PR China.
  • 2 Department of Infection, People's Hospital Affiliated to Shanxi Medical University, Taiyuan 030012, Shanxi, PR China.
  • 3 Department of Cell Biology, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, Shanxi, PR China.
  • 4 The Second Department of Gastroenterology, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, Shanxi, PR China. Electronic address: yangmudan6000@163.com.
  • 5 Graduate School of Shanxi Medical University, Taiyuan 030013, Shanxi, PR China; Department of Gastroenterology, People's Hospital Affiliated to Shanxi Medical University, Taiyuan 030012, Shanxi, PR China. Electronic address: W_Junping2221@126.com.
PMID: 35182680 DOI: 10.1016/j.gene.2022.146317
Abstract

Kinesin family member 4A (KIF4A), located in the human chromosome band Xq13.1, is aberrantly overexpressed in various cancers. Our study intended to assess the expression of KIF4A in insulinoma and to gain new insights into the molecular mechanisms of this rare disease. First, KIF4A was significantly recruited in pancreatic endocrine cells relative to Other cell types. A significant correlation existed between the overexpression of KIF4A and the poor survival of pancreatic adenocarcinoma patients. As revealed by CCK-8, TUNEL assay, flow cytometry, wound healing, Matrigel-transwell, senescence-associated β-galactosidase staining, ELISA, and subcutaneous tumor formation analysis in nude mice, knocking down KIF4A significantly inhibited the growth and metastasis of insulinoma cells in vivo and in vitro. Mechanistically, we observed that KIF4A promoter sequences had reduced H3K27me3 modifications, and decline in enhancer of zeste homolog-2 (EZH2) expression promoted KIF4A expression by reducing the modification, thus leading to insulinoma. Moreover, EZH2 knockdown-induced insulinoma cell proliferation was dependent on KIF4A overexpression since KIF4A knockdown eradicated shEZH2-induced proliferation of insulinoma cells. In summary, KIF4A was identified as a possible therapeutic target for insulinoma.

Keywords

EZH2; Epigenetics; H3K27me3; Insulinoma; KIF4A.

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