DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism
Abstract The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05291-w |
| _version_ | 1811226802541035520 |
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| author | Zhenzhen Li Yue Tan Xiang Li Jing Quan Ann M. Bode Ya Cao Xiangjian Luo |
| author_facet | Zhenzhen Li Yue Tan Xiang Li Jing Quan Ann M. Bode Ya Cao Xiangjian Luo |
| author_sort | Zhenzhen Li |
| collection | DOAJ |
| description | Abstract The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway. |
| first_indexed | 2024-04-12T09:31:20Z |
| format | Article |
| id | doaj.art-6347c1bd199f4478bdae972df09473c9 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T09:31:20Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6347c1bd199f4478bdae972df09473c92022-12-22T03:38:21ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011010.1038/s41419-022-05291-wDHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolismZhenzhen Li0Yue Tan1Xiang Li2Jing Quan3Ann M. Bode4Ya Cao5Xiangjian Luo6Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South UniversityHengyang Medical College, University of South ChinaDepartment of Pathology, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South UniversityThe Hormel Institute, University of MinnesotaKey Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South UniversityKey Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Nuclear Medicine, Xiangya Hospital, Central South UniversityAbstract The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway.https://doi.org/10.1038/s41419-022-05291-w |
| spellingShingle | Zhenzhen Li Yue Tan Xiang Li Jing Quan Ann M. Bode Ya Cao Xiangjian Luo DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism Cell Death and Disease |
| title | DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism |
| title_full | DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism |
| title_fullStr | DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism |
| title_full_unstemmed | DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism |
| title_short | DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism |
| title_sort | dhrs2 inhibits cell growth and metastasis in ovarian cancer by downregulation of chkα to disrupt choline metabolism |
| url | https://doi.org/10.1038/s41419-022-05291-w |
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