BRD7 inhibits the Warburg effect and tumor progression through inactivation of HIF1\u03b1/LDHA axis in breast cancer

Weihong Niu,Xinye Wang,Shanshan Liu,Hui Li,Xiaoling Li,Guiyuan Li,Chao Ren ,Jianglei Li,Ming Tan,Shanghelin Yin,Yao Zhou,Zheng Li,Yanwei Luo,Ran Zhao,Yukun Liu,Songqing Fan,Wei Xiong,Yukui Fu ,Heran Wang,Ming Zhou

doi:10.1038/s41419-018-0536-7

Abstract

The bromodomain-containing protein 7 (BRD7) was first identified as a tumor suppressor in nasopharyngeal carcinoma and has critical roles in cancer development and progression. However, the regulatory roles and mechanisms of BRD7 in cancer metabolism are still unknown. In this study, we demonstrated that BRD7 was lowly expressed in breast cancer tissues and was identified as a poor prognostic factor in breast cancer. Meanwhile, BRD7 could suppress cell proliferation, initiate cell apoptosis and reduce aerobic glycolysis, suggesting that BRD7 plays a tumor suppressive roles in breast cancer. Mechanistically, BRD7 could negatively regulate a critical glycolytic enzyme LDHA through directly interaction with its upstream transcription factor, HIF1α, facilitating degradation of HIF1α mediated by ubiquitin–proteasome pathway. Moreover, restoring the expression of LDHA in breast cancer cells could reverse the effect of BRD7 on aerobic glycolysis, cell proliferation, and tumor formation, as well as the expression of cell cycle and apopotosis related molecules such as cyclin D1, CDK4, P21, and c-PARP both in vitro and in vivo. Taken together, these results indicate that BRD7 acts as a tumor suppressor in breast cancer and represses the glycolysis and tumor progression through inactivation of HIF1α/LDHA transcription axis.

Highlights

Bromodomain-containing proteins are a class of evolutionarily conserved proteins that includes bromodomain-containing protein 7 (BRD7)
Reinstating BRD7 levels in the liver restores X-box binding protein 1 (XBP1) nuclear translocation, improves glucose homeostasis[12], and reduces the blood glucose levels in obese and diabetic mouse models[13], which is consistent with the result of the recent paper, the role of BRD7 in embryo development and glucose metabolism, suggesting that BRD7 is implicated in cellular energy metabolism mechanisms such as glycolysis
We found that lactate dehydrogenase A (LDHA) was negatively regulated by BRD7 through promoting proteasomal degradation of Hypoxia-inducible factor 1α (HIF1α), and restoring the expression of LDHA in BRD7overexpressed or breast cancer cells could reverse the effect of BRD7 on aerobic glycolysis, cell proliferation, and apoptosis, as well as the expression of cell cycle and apopotosis related molecules such as cyclin D1, CDK4, P21, and c-poly-ADP-ribose polymerase (c-PARP) both in vitro and in vivo

Summary

Introduction

Bromodomain-containing proteins are a class of evolutionarily conserved proteins that includes bromodomain-containing protein 7 (BRD7). Since our group first cloned this gene from nasopharyngeal carcinoma (NPC) cells in 2000, numerous studies have shown that BRD7 plays critical roles in cancer development and progression[1,2,3]. Interaction of BRD7 and p53 is essential for the transcriptional activation of some target genes of p53, Official journal of the Cell Death Differentiation Association. Hypoxia-inducible factor 1α (HIF1α) takes part in the reprogramming of cancer metabolism by regulating key molecules, including LDHA, SLC2A1, SLC2A3, HK1, HK2, and MCT4 in glucose metabolism[14,15]. Insulin, insulin-like growth factor (IGF)-1 or IGF-2, v-Src, lactate, pyruvate, and genetic alterations such as oncogene activation or tumor suppressor gene inactivation lead to HIF1α overexpression[14,16]

Methods

Results

Conclusion