SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling
The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tum...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/8/7150 |
| _version_ | 1797605189568430080 |
|---|---|
| author | Weida Wang Mingjin Wang Tingting Du Zhenyan Hou Shen You Sen Zhang Ming Ji Nina Xue Xiaoguang Chen |
| author_facet | Weida Wang Mingjin Wang Tingting Du Zhenyan Hou Shen You Sen Zhang Ming Ji Nina Xue Xiaoguang Chen |
| author_sort | Weida Wang |
| collection | DOAJ |
| description | The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells’ hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment. |
| first_indexed | 2024-03-11T04:57:35Z |
| format | Article |
| id | doaj.art-e3db007ee5e04c96ad2600bb6e145fe1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:57:35Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e3db007ee5e04c96ad2600bb6e145fe12023-11-17T19:35:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248715010.3390/ijms24087150SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 SignalingWeida Wang0Mingjin Wang1Tingting Du2Zhenyan Hou3Shen You4Sen Zhang5Ming Ji6Nina Xue7Xiaoguang Chen8Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaInstitute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaThe metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells’ hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.https://www.mdpi.com/1422-0067/24/8/7150gastric cancerSHMT2HIF1αredox balanceprogression |
| spellingShingle | Weida Wang Mingjin Wang Tingting Du Zhenyan Hou Shen You Sen Zhang Ming Ji Nina Xue Xiaoguang Chen SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling International Journal of Molecular Sciences gastric cancer SHMT2 HIF1α redox balance progression |
| title | SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling |
| title_full | SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling |
| title_fullStr | SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling |
| title_full_unstemmed | SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling |
| title_short | SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling |
| title_sort | shmt2 promotes gastric cancer development through regulation of hif1α vegf stat3 signaling |
| topic | gastric cancer SHMT2 HIF1α redox balance progression |
| url | https://www.mdpi.com/1422-0067/24/8/7150 |
| work_keys_str_mv | AT weidawang shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT mingjinwang shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT tingtingdu shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT zhenyanhou shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT shenyou shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT senzhang shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT mingji shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT ninaxue shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling AT xiaoguangchen shmt2promotesgastriccancerdevelopmentthroughregulationofhif1avegfstat3signaling |