D-2-hydroxyglutarate Dehydrogenase in Breast Carcinoma As a Potent Prognostic Marker Associated with Proliferation

Overview

Journal Histol Histopathol

Specialties Anatomy & Histology
Pathology

Date 2021 Jul 23

PMID 34296423

Citations 8

Authors

Chiaki Hayashi

Kiyoshi Takagi

Ai Sato

Mio Yamaguchi

Hiroyuki Minemura

Yasuhiro Miki

Narumi Harada-Shoji

Minoru Miyashita

Hironobu Sasano

Takashi Suzuki

Affiliations

Soon will be listed here.

Abstract

Background: D-2-hydroxyglutarate dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the regulation of cellular energy and biosynthetic intermediates. Previously, D2HGDH was reported to decrease 2-hydroxyglutarate level in breast carcinoma cells, but no other report has examined D2HGDH in breast carcinoma, and its significance remains unknown.

Methods: We first immunolocalized D2HGDH in 224 invasive breast carcinomas and evaluated its clinicopathological significance. We next examined associations between gene expression of D2HGDH and α-ketoglutarate-dependent dioxygenases in 23 breast carcinoma tissues using the gene expression profile data. Finally, we examined the effects of D2HGDH on the proliferation in three breast carcinoma cells.

Results: D2HGDH immunoreactivity was detected in 49% of invasive breast carcinomas, and the immunohistochemical D2HGDH status was positively associated with histological grade, HER2 and Ki-67, while it was inversely associated with estrogen receptor. Moreover, it was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both the disease-free and breast cancer-specific survival in these patients. Gene expression profile data revealed that D2HGDH expression was positively associated with the expression of 6 α-ketoglutarate-dependent dioxygenases (KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and ALKBH7). Consequent in vitro experiments demonstrated that D2HGDH overexpression significantly increased the cell proliferation activity of MCF-7, T47D and MDA-MB-231 cells.

Conclusion: These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of α-ketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.

Citing Articles

ALKBH1: emerging biomarker and therapeutic target for cancer treatment.

Xiao M, Fu J, Bo L, Li Y, Lin Z, Chen Z Discov Oncol. 2024; 15(1):816.

PMID: 39704856 PMC: 11662130. DOI: 10.1007/s12672-024-01696-5.

Regulation of Stromal Cells by Sex Steroid Hormones in the Breast Cancer Microenvironment.

Yamaguchi-Tanaka M, Takagi K, Sato A, Yamazaki Y, Miyashita M, Masamune A Cancers (Basel). 2024; 16(23).

PMID: 39682229 PMC: 11639972. DOI: 10.3390/cancers16234043.

Integrative pan-cancer analysis reveals the prognostic and immunotherapeutic value of ALKBH7 in HNSC.

Wang T, Lin B, Cai B, Cao Z, Liang C, Wu S Aging (Albany NY). 2024; 16(19):12781-12805.

PMID: 39400540 PMC: 11501379. DOI: 10.18632/aging.205981.

neomorphic mutation confers sensitivity to vitamin B12 in .

Ponomarova O, Starbard A, Belfi A, Anderson A, Sundaram M, Walhout A Life Sci Alliance. 2024; 7(10).

PMID: 39009411 PMC: 11249921. DOI: 10.26508/lsa.202402924.

Sato A, Takagi K, Yoshimura A, Tsukamoto W, Yamaguchi-Tanaka M, Miki Y Int J Mol Sci. 2023; 24(9).

PMID: 37176127 PMC: 10179240. DOI: 10.3390/ijms24098419.

References

Achouri Y, Noel G, Vertommen D, Rider M, Veiga-da-Cunha M, Van Schaftingen E . Identification of a dehydrogenase acting on D-2-hydroxyglutarate. Biochem J. 2004; 381(Pt 1):35-42. PMC: 1133759. DOI: 10.1042/BJ20031933. View

Anderson N, Mucka P, Kern J, Feng H . The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2017; 9(2):216-237. PMC: 5818369. DOI: 10.1007/s13238-017-0451-1. View

Baksh S, Finley L . Metabolic Coordination of Cell Fate by α-Ketoglutarate-Dependent Dioxygenases. Trends Cell Biol. 2020; 31(1):24-36. PMC: 7748998. DOI: 10.1016/j.tcb.2020.09.010. View

Chang W, Forde D, Lai A . Dual prognostic role of 2-oxoglutarate-dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance. Cancer Commun (Lond). 2019; 39(1):23. PMC: 6489267. DOI: 10.1186/s40880-019-0369-5. View

Chen M, Hsu L, Wang S, Hsu C, Lee H, Tseng L . ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation. Cells. 2020; 9(7). PMC: 7407809. DOI: 10.3390/cells9071598. View

Davidson A, Chia S, Olson R, Nichol A, Speers C, Coldman A . Stage, treatment and outcomes for patients with breast cancer in British Columbia in 2002: a population-based cohort study. CMAJ Open. 2014; 1(4):E134-41. PMC: 3985980. DOI: 10.9778/cmajo.20130017. View

de Azambuja E, Cardoso F, de Castro Jr G, Colozza M, Mano M, Durbecq V . Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer. 2007; 96(10):1504-13. PMC: 2359936. DOI: 10.1038/sj.bjc.6603756. View

Djalalov S, Beca J, Amir E, Krahn M, Trudeau M, Hoch J . Economic evaluation of hormonal therapies for postmenopausal women with estrogen receptor-positive early breast cancer in Canada. Curr Oncol. 2015; 22(2):84-96. PMC: 4399616. DOI: 10.3747/co.22.2120. View

Elia I, Rossi M, Stegen S, Broekaert D, Doglioni G, van Gorsel M . Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature. 2019; 568(7750):117-121. PMC: 6451642. DOI: 10.1038/s41586-019-0977-x. View

10.

Hammond M, Hayes D, Dowsett M, Allred D, Hagerty K, Badve S . American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010; 134(7):e48-72. DOI: 10.5858/134.7.e48. View

11.

Krell D, Assoku M, Galloway M, Mulholland P, Tomlinson I, Bardella C . Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma. PLoS One. 2011; 6(5):e19868. PMC: 3100313. DOI: 10.1371/journal.pone.0019868. View

12.

Lin A, Abbas S, Kim S, Ortega M, Bouamar H, Escobedo Y . D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2. Nat Commun. 2015; 6:7768. PMC: 4515030. DOI: 10.1038/ncomms8768. View

13.

Liu J, Xu W, Li S, Sun R, Cheng W . Multi-omics analysis of tumor mutational burden combined with prognostic assessment in epithelial ovarian cancer based on TCGA database. Int J Med Sci. 2020; 17(18):3200-3213. PMC: 7646107. DOI: 10.7150/ijms.50491. View

14.

Matsunaga H, Futakuchi-Tsuchida A, Takahashi M, Ishikawa T, Tsuji M, Ando O . IDH1 and IDH2 have critical roles in 2-hydroxyglutarate production in D-2-hydroxyglutarate dehydrogenase depleted cells. Biochem Biophys Res Commun. 2012; 423(3):553-6. DOI: 10.1016/j.bbrc.2012.06.002. View

15.

Mishra P, Tang W, Putluri V, Dorsey T, Jin F, Wang F . ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest. 2017; 128(1):323-340. PMC: 5749504. DOI: 10.1172/JCI93815. View

16.

Nagasaki S, Suzuki T, Miki Y, Akahira J, Kitada K, Ishida T . 17Beta-hydroxysteroid dehydrogenase type 12 in human breast carcinoma: a prognostic factor via potential regulation of fatty acid synthesis. Cancer Res. 2009; 69(4):1392-9. DOI: 10.1158/0008-5472.CAN-08-0821. View

17.

Querzoli P, Pedriali M, Rinaldi R, Secchiero P, Rossi P, Kuhn E . as an Adjunct Prognostic Factor in Breast Cancer Patients with Less Aggressive Disease: A Study with a Review of the Literature. Diagnostics (Basel). 2021; 11(4). PMC: 8066261. DOI: 10.3390/diagnostics11040604. View

18.

Ramadoss S, Guo G, Wang C . Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53. Oncogene. 2016; 36(1):47-59. PMC: 5140781. DOI: 10.1038/onc.2016.174. View

19.

Sato-Tadano A, Suzuki T, Amari M, Takagi K, Miki Y, Tamaki K . Hexokinase II in breast carcinoma: a potent prognostic factor associated with hypoxia-inducible factor-1α and Ki-67. Cancer Sci. 2013; 104(10):1380-8. PMC: 7656546. DOI: 10.1111/cas.12238. View

20.

Takagi K, Miki Y, Shibahara Y, Nakamura Y, Ebata A, Watanabe M . BUB1 immunolocalization in breast carcinoma: its nuclear localization as a potent prognostic factor of the patients. Horm Cancer. 2013; 4(2):92-102. PMC: 10358026. DOI: 10.1007/s12672-012-0130-x. View