D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation

Chiaki Hayashi, Kiyoshi Takagi, Ai Sato, Mio Yamaguchi, Hiroyuki Minemura, Yasuhiro Miki, Narumi Harada-Shoji, Minoru Miyashita, Hironobu Sasano, Takashi Suzuki

Research output: Contribution to journalArticlepeer-review

Abstract

Summary. 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 αketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.

Original languageEnglish
Pages (from-to)1053-1062
Number of pages10
JournalHistology and Histopathology
Volume36
Issue number10
DOIs
Publication statusPublished - 2021 Oct

Keywords

  • Breast cancer
  • D-2-hydroxyglutarate dehydrogenase (D2HGDH)
  • Immunohistochemistry
  • Prognosis
  • Proliferation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology

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