YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration
Abstract KRAS-driven metabolic reprogramming is a known peculiarity features of pancreatic ductal adenocarcinoma (PDAC) cells. However, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed significantly elevated expression of YY...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-022-02712-w |
| _version_ | 1811258826236624896 |
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| author | Bin Li Junyi Wang Jing Liao Minghui Wu Xiangshu Yuan Hezhi Fang Lijun Shen Minghua Jiang |
| author_facet | Bin Li Junyi Wang Jing Liao Minghui Wu Xiangshu Yuan Hezhi Fang Lijun Shen Minghua Jiang |
| author_sort | Bin Li |
| collection | DOAJ |
| description | Abstract KRAS-driven metabolic reprogramming is a known peculiarity features of pancreatic ductal adenocarcinoma (PDAC) cells. However, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed significantly elevated expression of YY1 in human PDAC tissues, which positively correlated with a poor disease progression. Furthermore, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion led to impaired mitochondrial RNA expression, which further inhibited mitochondrial oxidative phosphorylation (OXPHOS) complex assembly and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function reduced the generation of aspartate, an output of the tricarboxylic acid cycle (TCA), and resulted in the inhibition of cell proliferation owing to unavailability of aspartate-associated nucleotides. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Our findings suggest that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. Thus, targeting nucleotide biosynthesis is a promising strategy for PDAC treatment. |
| first_indexed | 2024-04-12T18:20:22Z |
| format | Article |
| id | doaj.art-1db8785e1ded4051bf6b7dde1b411482 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-12T18:20:22Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-1db8785e1ded4051bf6b7dde1b4114822022-12-22T03:21:27ZengBMCCancer Cell International1475-28672022-09-0122111310.1186/s12935-022-02712-wYY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respirationBin Li0Junyi Wang1Jing Liao2Minghui Wu3Xiangshu Yuan4Hezhi Fang5Lijun Shen6Minghua Jiang7Department of Laboratory Medicine, The Second Affiliated Hospital, Wenzhou Medical UniversityDepartment of Clinical Laboratory Examination, The Seventh Affiliated Hospital, Sun Yat-Sen UniversityKey Laboratory of Laboratory Medicine, Ministry of Education; Zhejiang Provincial Key Laboratory of Medical Genetics; College of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Laboratory Medicine, The Second Affiliated Hospital, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education; Zhejiang Provincial Key Laboratory of Medical Genetics; College of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityKey Laboratory of Laboratory Medicine, Ministry of Education; Zhejiang Provincial Key Laboratory of Medical Genetics; College of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversitySchool of Laboratory Medicine and Life Sciences, Wenzhou Medical UniversityDepartment of Laboratory Medicine, The Second Affiliated Hospital, Wenzhou Medical UniversityAbstract KRAS-driven metabolic reprogramming is a known peculiarity features of pancreatic ductal adenocarcinoma (PDAC) cells. However, the metabolic roles of other oncogenic genes, such as YY1, in PDAC development are still unclear. In this study, we observed significantly elevated expression of YY1 in human PDAC tissues, which positively correlated with a poor disease progression. Furthermore, in vitro studies confirmed that YY1 deletion inhibited PDAC cell proliferation and tumorigenicity. Moreover, YY1 deletion led to impaired mitochondrial RNA expression, which further inhibited mitochondrial oxidative phosphorylation (OXPHOS) complex assembly and altered cellular nucleotide homeostasis. Mechanistically, the impairment of mitochondrial OXPHOS function reduced the generation of aspartate, an output of the tricarboxylic acid cycle (TCA), and resulted in the inhibition of cell proliferation owing to unavailability of aspartate-associated nucleotides. Conversely, exogenous supplementation with aspartate fully restored PDAC cell proliferation. Our findings suggest that YY1 promotes PDAC cell proliferation by enhancing mitochondrial respiration and the TCA, which favors aspartate-associated nucleotide synthesis. Thus, targeting nucleotide biosynthesis is a promising strategy for PDAC treatment.https://doi.org/10.1186/s12935-022-02712-wYY1PDACOXPHOSNucleotide metabolismAspartate |
| spellingShingle | Bin Li Junyi Wang Jing Liao Minghui Wu Xiangshu Yuan Hezhi Fang Lijun Shen Minghua Jiang YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration Cancer Cell International YY1 PDAC OXPHOS Nucleotide metabolism Aspartate |
| title | YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| title_full | YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| title_fullStr | YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| title_full_unstemmed | YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| title_short | YY1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| title_sort | yy1 promotes pancreatic cancer cell proliferation by enhancing mitochondrial respiration |
| topic | YY1 PDAC OXPHOS Nucleotide metabolism Aspartate |
| url | https://doi.org/10.1186/s12935-022-02712-w |
| work_keys_str_mv | AT binli yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT junyiwang yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT jingliao yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT minghuiwu yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT xiangshuyuan yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT hezhifang yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT lijunshen yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration AT minghuajiang yy1promotespancreaticcancercellproliferationbyenhancingmitochondrialrespiration |