Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells. APPROACH AND RESULTS: We used a CRISPR librar...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022
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| Online Access: | https://hdl.handle.net/1721.1/143563 |
| _version_ | 1826195305739059200 |
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| author | Jiang, Tingting Sánchez-Rivera, Francisco J Soto-Feliciano, Yadira M Yang, Qiyuan Song, Chun-Qing Bhuatkar, Arjun Haynes, Cole M Hemann, Michael T Xue, Wen |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Jiang, Tingting Sánchez-Rivera, Francisco J Soto-Feliciano, Yadira M Yang, Qiyuan Song, Chun-Qing Bhuatkar, Arjun Haynes, Cole M Hemann, Michael T Xue, Wen |
| author_sort | Jiang, Tingting |
| collection | MIT |
| description | BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells. APPROACH AND RESULTS: We used a CRISPR library targeting ~2,000 druggable genes to perform a high-throughput screen and identified adenylosuccinate lyase (ADSL), a key enzyme involved in the de novo purine synthesis pathway, as a potential drug target for HCC. ADSL has been implicated as a potential oncogenic driver in some cancers, but its role in liver cancer progression remains unknown. CRISPR-mediated knockout of ADSL impaired colony formation of liver cancer cells by affecting AMP production. In the absence of ADSL, the growth of liver tumors is retarded in vivo. Mechanistically, we found that ADSL knockout caused S-phase cell cycle arrest not by inducing DNA damage but by impairing mitochondrial function. Using data from patients with HCC, we also revealed that high ADSL expression occurs during tumorigenesis and is linked to poor survival rate. CONCLUSIONS: Our findings uncover the role of ADSL-mediated de novo purine synthesis in fueling mitochondrial ATP production to promote liver cancer cell growth. Targeting ADSL may be a therapeutic approach for patients with HCC. |
| first_indexed | 2024-09-23T10:10:37Z |
| format | Article |
| id | mit-1721.1/143563 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:10:37Z |
| publishDate | 2022 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1435632023-04-07T19:42:57Z Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function Jiang, Tingting Sánchez-Rivera, Francisco J Soto-Feliciano, Yadira M Yang, Qiyuan Song, Chun-Qing Bhuatkar, Arjun Haynes, Cole M Hemann, Michael T Xue, Wen Whitehead Institute for Biomedical Research BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is among the most common cancer types worldwide, yet patients with HCC have limited treatment options. There is an urgent need to identify drug targets that specifically inhibit the growth of HCC cells. APPROACH AND RESULTS: We used a CRISPR library targeting ~2,000 druggable genes to perform a high-throughput screen and identified adenylosuccinate lyase (ADSL), a key enzyme involved in the de novo purine synthesis pathway, as a potential drug target for HCC. ADSL has been implicated as a potential oncogenic driver in some cancers, but its role in liver cancer progression remains unknown. CRISPR-mediated knockout of ADSL impaired colony formation of liver cancer cells by affecting AMP production. In the absence of ADSL, the growth of liver tumors is retarded in vivo. Mechanistically, we found that ADSL knockout caused S-phase cell cycle arrest not by inducing DNA damage but by impairing mitochondrial function. Using data from patients with HCC, we also revealed that high ADSL expression occurs during tumorigenesis and is linked to poor survival rate. CONCLUSIONS: Our findings uncover the role of ADSL-mediated de novo purine synthesis in fueling mitochondrial ATP production to promote liver cancer cell growth. Targeting ADSL may be a therapeutic approach for patients with HCC. 2022-06-27T17:25:50Z 2022-06-27T17:25:50Z 2021 2022-06-27T16:31:51Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/143563 Jiang, Tingting, Sánchez-Rivera, Francisco J, Soto-Feliciano, Yadira M, Yang, Qiyuan, Song, Chun-Qing et al. 2021. "Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function." Hepatology, 74 (1). en 10.1002/HEP.31685 Hepatology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | Jiang, Tingting Sánchez-Rivera, Francisco J Soto-Feliciano, Yadira M Yang, Qiyuan Song, Chun-Qing Bhuatkar, Arjun Haynes, Cole M Hemann, Michael T Xue, Wen Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title | Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title_full | Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title_fullStr | Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title_full_unstemmed | Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title_short | Targeting the De Novo Purine Synthesis Pathway Through Adenylosuccinate Lyase Depletion Impairs Liver Cancer Growth by Perturbing Mitochondrial Function |
| title_sort | targeting the de novo purine synthesis pathway through adenylosuccinate lyase depletion impairs liver cancer growth by perturbing mitochondrial function |
| url | https://hdl.handle.net/1721.1/143563 |
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