Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment
Abstract Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their met...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-12-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202202104 |
| _version_ | 1828277274990870528 |
|---|---|
| author | Chunxue Yang Derek Lee Misty Shuo Zhang Aki Pui‐Wah Tse Lai Wei Macus Hao‐Ran Bao Bowie Po‐Yee Wong Cerise Yuen‐Ki Chan Vincent Wai‐Hin Yuen Yiling Chen Carmen Chak‐Lui Wong |
| author_facet | Chunxue Yang Derek Lee Misty Shuo Zhang Aki Pui‐Wah Tse Lai Wei Macus Hao‐Ran Bao Bowie Po‐Yee Wong Cerise Yuen‐Ki Chan Vincent Wai‐Hin Yuen Yiling Chen Carmen Chak‐Lui Wong |
| author_sort | Chunxue Yang |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their metabolic pathways for rapid adaptations. The efficiency of dietary glutamine deficiency as HCC treatment is examined and the adaptation machinery under glutamine depletion in HCC cells is unraveled. Using genome‐wide CRISPR/Cas9 knockout library screening, this study identifies that pyruvate dehydrogenase α (PDHA), pyruvate dehydrogenase β (PDHB), and pyruvate carboxylase (PC) in pyruvate metabolism are crucial to the adaptation of glutamine depletion in HCC cells. Knockout of either PDHA, PDHB or PC induced metabolic reprogramming of the tricarboxylic acid (TCA) cycle, disrupts mitochondrial function, leading to the suppression of HCC cell proliferation under glutamine depletion. Surprisingly, dietary glutamine restriction improves therapeutic responses of HCC to PDH or PC inhibitor in mouse HCC models. Stable isotope carbon tracing confirms that PDH or PC inhibitors further disrupt the metabolic rewiring of the TCA cycle induced by dietary glutamine depletion in HCC. In summary, the results demonstrate that pyruvate metabolism acts as novel targetable metabolic vulnerabilities for HCC treatment in combination with a glutamine‐deficient diet. |
| first_indexed | 2024-04-13T07:10:53Z |
| format | Article |
| id | doaj.art-2d925d402ae14ea8b4d8d8c10e13c325 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-13T07:10:53Z |
| publishDate | 2022-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-2d925d402ae14ea8b4d8d8c10e13c3252022-12-22T02:56:52ZengWileyAdvanced Science2198-38442022-12-01934n/an/a10.1002/advs.202202104Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer TreatmentChunxue Yang0Derek Lee1Misty Shuo Zhang2Aki Pui‐Wah Tse3Lai Wei4Macus Hao‐Ran Bao5Bowie Po‐Yee Wong6Cerise Yuen‐Ki Chan7Vincent Wai‐Hin Yuen8Yiling Chen9Carmen Chak‐Lui Wong10Department of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaDepartment of Pathology The University of Hong Kong Hong Kong P. R. ChinaAbstract Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Glutamine is an essential, extracellular nutrient which supports HCC growth. Dietary glutamine deficiency may be a potential therapeutic approach for HCC. HCC cells overcome metabolic challenges by rewiring their metabolic pathways for rapid adaptations. The efficiency of dietary glutamine deficiency as HCC treatment is examined and the adaptation machinery under glutamine depletion in HCC cells is unraveled. Using genome‐wide CRISPR/Cas9 knockout library screening, this study identifies that pyruvate dehydrogenase α (PDHA), pyruvate dehydrogenase β (PDHB), and pyruvate carboxylase (PC) in pyruvate metabolism are crucial to the adaptation of glutamine depletion in HCC cells. Knockout of either PDHA, PDHB or PC induced metabolic reprogramming of the tricarboxylic acid (TCA) cycle, disrupts mitochondrial function, leading to the suppression of HCC cell proliferation under glutamine depletion. Surprisingly, dietary glutamine restriction improves therapeutic responses of HCC to PDH or PC inhibitor in mouse HCC models. Stable isotope carbon tracing confirms that PDH or PC inhibitors further disrupt the metabolic rewiring of the TCA cycle induced by dietary glutamine depletion in HCC. In summary, the results demonstrate that pyruvate metabolism acts as novel targetable metabolic vulnerabilities for HCC treatment in combination with a glutamine‐deficient diet.https://doi.org/10.1002/advs.202202104CRISPR/Cas9 library screeningdietary interventionglutamine depletionhepatocellular carcinomapyruvate metabolism |
| spellingShingle | Chunxue Yang Derek Lee Misty Shuo Zhang Aki Pui‐Wah Tse Lai Wei Macus Hao‐Ran Bao Bowie Po‐Yee Wong Cerise Yuen‐Ki Chan Vincent Wai‐Hin Yuen Yiling Chen Carmen Chak‐Lui Wong Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment Advanced Science CRISPR/Cas9 library screening dietary intervention glutamine depletion hepatocellular carcinoma pyruvate metabolism |
| title | Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment |
| title_full | Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment |
| title_fullStr | Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment |
| title_full_unstemmed | Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment |
| title_short | Genome‐Wide CRISPR/Cas9 Library Screening Revealed Dietary Restriction of Glutamine in Combination with Inhibition of Pyruvate Metabolism as Effective Liver Cancer Treatment |
| title_sort | genome wide crispr cas9 library screening revealed dietary restriction of glutamine in combination with inhibition of pyruvate metabolism as effective liver cancer treatment |
| topic | CRISPR/Cas9 library screening dietary intervention glutamine depletion hepatocellular carcinoma pyruvate metabolism |
| url | https://doi.org/10.1002/advs.202202104 |
| work_keys_str_mv | AT chunxueyang genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT dereklee genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT mistyshuozhang genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT akipuiwahtse genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT laiwei genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT macushaoranbao genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT bowiepoyeewong genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT ceriseyuenkichan genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT vincentwaihinyuen genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT yilingchen genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment AT carmenchakluiwong genomewidecrisprcas9libraryscreeningrevealeddietaryrestrictionofglutamineincombinationwithinhibitionofpyruvatemetabolismaseffectivelivercancertreatment |