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BRD7 Inhibits the Warburg Effect and Tumor Progression Through Niu et al. Cell Death and Disease (2018) 9:519 DOI 10.1038/s41419-018-0536-7 Cell Death & Disease ARTICLE Open Access Corrected: Retraction BRD7 inhibits the Warburg effect and tumor progression through inactivation of HIF1α/LDHA axis in breast cancer Weihong Niu1,2,3,YanweiLuo2,3,XinyeWang2,3, Yao Zhou2,3,HuiLi4,HeranWang1,3, Yaojie Fu5, Shanshan Liu5, Shanghelin Yin5, Jianglei Li5,RanZhao2,3, Yukun Liu2,3,SongqingFan4,ZhengLi2,3,6, Wei Xiong2,3, Xiaoling Li2,3, Guiyuan Li1,2,3, Caiping Ren3,MingTan 7 andMingZhou1,2,3 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 1234567890():,; 1234567890():,; 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. Introduction that BRD7 is involved in growth inhibition of NPC by Bromodomain-containing proteins are a class of inhibiting cell cycle progression from G1 to S, and thus evolutionarily conserved proteins that includes was identified as a tumor suppressor in NPC4,5. BRD7 is bromodomain-containing protein 7 (BRD7). Since our also involved in multiple physiological processes, includ- group first cloned this gene from nasopharyngeal carci- ing the regulation of spermatogenesis and cognitive – noma (NPC) cells in 2000, numerous studies have shown behavior6 8. BRD7 is downregulated in multiple types of that BRD7 plays critical roles in cancer development and tumor specimen and cancer cells, and might be involved – progression1 3. Our previous studies have demonstrated in the development and progression of multiple types of cancers, including breast cancer and prostate cancer1. BRD7 can bind to BRCA1 in breast cancer cells, which is Correspondence: Ming Tan ([email protected]) or Ming Zhou required for the BRCA1-mediated transcriptional regula- ([email protected]) tion of the estrogen receptor (ER), suggesting a close 1The Affiliated Tumor Hospital of Xiangya Medical School, Central South ’ relationship between BRD7 and breast cancer develop- University, Changsha, Hunan 410013, People s Republic of China 9 2The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, The ment . However, so far there is still no direct evidence to Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry show that BRD7 plays a role in breast cancer. of Education, Xiangya Hospital, Central South University, Changsha, Hunan Interaction of BRD7 and p53 is essential for the tran- 410078, People’s Republic of China Full list of author information is available at the end of the article scriptional activation of some target genes of p53, Edited by: A. Finazzi-Agrò © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Niu et al. Cell Death and Disease (2018) 9:519 Page 2 of 17 including p21 and MDM2, which is required for p53- progression through inactivation of HIF1α/LDHA tran- dependent oncogene-induced senescence10,11. Notably, scription axis. one study shows that BRD7 is capable of regulating X-box binding protein 1 (XBP1) nuclear translocation and Materials and Methods interacts with the regulatory subunits of phosphatidyl- Tissue samples and clinical data inositol3-kinase (PI3K) to increase the nuclear translo- All the human tissues were collected from the Second cation of both p85α/β and XBP1s. Reinstating BRD7 Xiangya Hospital of Central South University from levels in the liver restores XBP1s nuclear translocation, November 2001 to September 2012. This study was improves glucose homeostasis12, and ultimately reduces approved by the Committee on the Ethics of Central South the blood glucose levels in obese and diabetic mouse University. All of the individuals participating in this study models13, which is also consistent with the result of the have provided written informed consent. The samples recent paper, the role of BRD7 in embryo development were compiled into a tissue microarray as previously and glucose metabolism, suggesting that BRD7 is impli- described, which included 225 cases of breast cancer tis- – cated in cellular energy metabolism mechanisms such as sues and 61 cases of non-cancerous breast tissues18 20. glycolysis. However, the role of BRD7 in regulating cancer Clinicopathologic characteristics of breast cancer patients cell metabolism has not been systematically investigated. were recorded, including gender, age, clinical tumor node Hypoxia-inducible factor 1α (HIF1α) takes part in the metastasis (TNM) stage, pathology diagnosis, and mole- reprogramming of cancer metabolism by regulating key cular subtype. The profile of clinicopathologic character- molecules, including LDHA, SLC2A1, SLC2A3, HK1, istics of the breast cancer patients is shown in Table 1. HK2, and MCT4 in glucose metabolism14,15. The Patients’ ages ranged from 23 to 71 years old. All of the expression of HIF1α is high in multiple types of cancers, 225 breast cancer patients had valid follow-up data, and such as lung cancer, prostate cancer, breast cancer, and the longest survival time was 120 months. The overall colonic adenocarcinoma. In tumor progression, insulin, survival (OS) was defined as the time from diagnosis to the insulin-like growth factor (IGF)-1 or IGF-2, v-Src, lactate, date of death or the date last known alive. pyruvate, and genetic alterations such as oncogene acti- vation or tumor suppressor gene inactivation lead to Cell culture HIF1α overexpression14,16. Human breast cancer cell lines MCF-7, MDA-MB-231, Mounting evidence accumulated in cancer research has MDA-MB-453, and the human embryonic kidney cell line demonstrated that dysregulated cancer cell bioenergy plays an important role in the development and pro- 17 Table 1 Clinicopathologic characteristics of breast cancer gression of breast cancer . While currently there is no patients direct evidence to support a role of BRD7 in breast cancer and it is not clear whether BRD7 regulates cancer cell Age metabolism. Therefore, in this study we investigated Mean ± S.D. 46 ± 0.66 whether BRD7 indeed plays a role in breast cancer pro- gression and explored whether BRD7 regulates breast Sex (%) cancer cell metabolism. We revealed that BRD7 showed Male 0.4 (1/225) low expression in breast cancer tissues compared to Female 99.6 (224/225) normal tissue, and loss of BRD7 expression in breast Tumor size (%) cancer was identified as a poor prognostic factor. More- – over, ectopic expression of BRD7 in breast cancer cells T1 2 62.7 (141/225) suppressed cell proliferation, initiated cell apoptosis, and T3–4 37.3 (84/225) decreased glycolysis. Furthermore, we found that lactate Nodal metastasis (%) dehydrogenase A (LDHA) was negatively regulated by Present 74.2 (167/225) BRD7 through promoting proteasomal degradation of HIF1α, and restoring the expression of LDHA in BRD7- Absent 25.8 (58/225) overexpressed or breast cancer cells could reverse the Distant metastasis (%) effect of BRD7 on aerobic glycolysis, cell proliferation, and Present 9.3 (21/225) apoptosis, as well as the expression of cell cycle and Absent 81.7 (204/225) apopotosis related molecules such as cyclin D1, CDK4, P21, and c-poly-ADP-ribose polymerase (c-PARP) both TNM stage (%) in vitro and in vivo. Taken together, these results indicate I–II 65.8 (148/225) that BRD7 functions as a tumor suppressor gene in breast III–IV 34.2 (77/225) cancer and BRD7 inhibits aerobic glycolysis and tumor Official journal of the Cell Death Differentiation Association Niu et al. Cell Death and Disease (2018) 9:519 Page 3 of 17 HEK-293T were obtained from the American Type Cul- citric acid buffer (pH 6.0), heated in a microwave oven for ture Collection (Manassas, VA, USA). All cells were cul- 10 min, and then treated with 3% H2O2 for 15 min and tured in high glucose DMEM medium (Invitrogen Life washed with Tris-buffered saline containing 1% Tween 20 Technologies, Carlsbad, CA, USA) containing 10% fetal (TBST) three times each for 5 min. After a 60 min incu- bovine serum (FBS) (Gibco, Thermo Fisher Scientific, bation in normal goat serum (Boster, Wuhan, China), the Waltham, MA, USA), 100 units/ml penicillin and 100 mg/ slides were incubated with primary antibodies overnight ml streptomycin.
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