Abstract 1788: A high-throughput chemical genetic screen reveals SALL4-induced metabolic vulnerabilities in cancer
| العنوان: | Abstract 1788: A high-throughput chemical genetic screen reveals SALL4-induced metabolic vulnerabilities in cancer |
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| المؤلفون: | Giridharan Periyasamy, Bee Hui Liu, Li Chai, Yue Wu, Kol Jia Yong, May Yin Lee, Siyu Wang, Glenn Kunath Bonney, Justin L. Tan, Yoganathan Kanagasundaram, Atsushi Suzuki, Yun Shen Chan, Zi Hui Tan, John M. Asara, Zhi Han Lim, Tan Boon Toh, Chan-Shuo Wu, Nikki R. Kong, Feng Li, Hon Man Chan, Yock Young Dan, Guo-Dong Lu, Edward Kai-Hua Chow, Alicia Stein, Wai Leong Tam, Huck-Hui Ng, Lissa Hooi, Guo Hao Ng, Siew Bee Ng, Joanna Z. Yeo, Chung Yan Leong, Daniel Geoffrey Tenen, Matan Thangavelu Thangavelu, Hong Kee Tan, Kia Ngee Low, Mahmoud A. Bassal, Siming Ma |
| المصدر: | Cancer Research. 80:1788-1788 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer Research, Oncology, SALL4, Computer science, medicine, Cancer, Computational biology, medicine.disease, Throughput (business), Genetic screen |
| الوصف: | Transcription factors are important drivers of cancer but the development of therapeutics against these factors has had limited success. We developed a stringent high-throughput chemical genetic screening platform to identify compounds that target oncogenic transcription factor SALL4 dependency in liver cancer. The platform comprises SALL4 low- and high-expressing endogenous and engineered isogenic liver cancer cell lines. Unexpectedly, from screening 21,575 natural product extracts, the top hits were four oxidative phosphorylation inhibitors that selectively reduced SALL4-dependent cell viability. The ATP synthase inhibitor oligomycin suppressed SALL4-expressing cancer in lung and liver cancer cell culture models, and in patient-derived xenograft models of liver cancer. Oligomycin also synergized with sorafenib, the standard-of-care targeted therapy in liver cancer, to effectively suppress SALL4-driven tumorigenesis in vivo. When aberrantly expressed in cancer, SALL4 binds ~50% of mitochondrial genes, including many oxidative phosphorylation genes, to predominantly upregulate their expression. SALL4 upregulation also alters the levels of oxidative phosphorylation-related metabolites and functionally increases oxidative phosphorylation activity. Application of our endogenous/isogenic transcription factor-screening platform revealed a therapeutically actionable oxidative phosphorylation vulnerability in SALL4-expressing cancers. Citation Format: Justin L. Tan, Feng Li, Joanna Z. Yeo, Kol Jia Yong, Mahmoud A. Bassal, Guo Hao Ng, May Yin Lee, Chung Yan Leong, Hong Kee Tan, Chan-Shuo Wu, Bee Hui Liu, Hon Man Chan, Zi Hui Tan, Yun Shen Chan, Siyu Wang, Zhi Han Lim, Tan Boon Toh, Lissa Hooi, Kia Ngee Low, Siming Ma, Nikki R. Kong, Alicia J. Stein, Yue Wu, Matan T. Thangavelu, Atsushi Suzuki, Giridharan Periyasamy, John M. Asara, Yock Young Dan, Glenn K. Bonney, Edward K. Chow, Guo-Dong Lu, Huck Hui Ng, Yoganathan Kanagasundaram, Siew Bee Ng, Wai Leong Tam, Li Chai, Daniel G. Tenen. A high-throughput chemical genetic screen reveals SALL4-induced metabolic vulnerabilities in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1788. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::dd90ae5e89b8c585e18c405d1916ad4c https://doi.org/10.1158/1538-7445.am2020-1788 |
| رقم الأكسشن: | edsair.doi...........dd90ae5e89b8c585e18c405d1916ad4c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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