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Interaction of EZH2 and P65 is involved in the arsenic trioxide-induced anti-angiogenesis in human triple-negative breast cancer cells

Abstract

Breast cancer (BC) is the most common female malignancy in the world. Triple-negative breast cancer (TNBC) is a subtype of BC characterized by the lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2 (HER-2), resulting in the limited therapeutic options. Due to the aggressive behaviors at early stage, TNBC exhibits poorer outcomes compared to other BC subtypes. Hematogenous metastasis, which spreads cancerous cells to lungs and/or bones, plays a pivotal role in the progression of TNBC. Therefore, it is of great importance to study the anti-angiogenesis regulation mechanism for finding new treatment options for TNBC. Arsenic trioxide (ATO) exhibits anti-cancer effect on solid tumors, including TNBC. However, the roles and the molecular mechanism of ATO in the anti-angiogenesis of TNBC remain less well documented. Our data showed that ATO restrained the expression and secretion of vascular endothelial growth factor (VEGF) and impaired the angiogenic ability in TNBC cells. In addition, ATO suppressed the angiogenic ability in TNBC by inhibiting the interaction of the enhancer of zeste homolog 2 (EZH2) with p65, downregulating the nuclear factor-κB (NF-κB) activity, hence contributing to the regulation of IL-6/Stat3 signaling pathway. All of our findings would help to better understand the mechanism of ATO anti-angiogenesis in TNBC, thus highlighting the therapeutic potential of ATO in TNBC by targeting angiogenesis.

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Abbreviations

ATO:

Arsenic trioxide

EZH2:

Enhancer of zeste homolog 2

HUVECs:

Human umbilical vein endothelial cells

TNBC:

Triple-negative breast cancer

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81703209, 81673205), the Postdoctoral Science Foundation of Jiangsu Province, China Postdoctoral Science Foundation (2017M621823, 2018T110548), the Major Program of Natural Science Research of Jiangsu Higher Education Institutions (15KJA330001), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Correspondence to Zhong Li.

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Jiang, F., Li, Y., Si, L. et al. Interaction of EZH2 and P65 is involved in the arsenic trioxide-induced anti-angiogenesis in human triple-negative breast cancer cells. Cell Biol Toxicol 35, 361–371 (2019). https://doi.org/10.1007/s10565-018-09458-0

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Keywords

  • Triple-negative breast cancer
  • Angiogenesis
  • Arsenic trioxide
  • NF-κB/IL-6/Stat3 signaling
  • EZH2