Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B
Abstract Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.269 |
| _version_ | 1797802531344089088 |
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| author | Na Sang Xi Zhong Kun Gou Huan Liu Jing Xu Yang Zhou Xia Zhou Yuanzhi Liu Zhiqian Chen Yue Zhou Yan Li Lei Tao Na Su Lingyun Zhou Jiahao Qiu Xinyu Yang Zeping Zuo Li Fu Jingyao Zhang Dan Li Cong Li Qingxiang Sun Jian Lei Rui Li Shengyong Yang Xiaobo Cen Yinglan Zhao |
| author_facet | Na Sang Xi Zhong Kun Gou Huan Liu Jing Xu Yang Zhou Xia Zhou Yuanzhi Liu Zhiqian Chen Yue Zhou Yan Li Lei Tao Na Su Lingyun Zhou Jiahao Qiu Xinyu Yang Zeping Zuo Li Fu Jingyao Zhang Dan Li Cong Li Qingxiang Sun Jian Lei Rui Li Shengyong Yang Xiaobo Cen Yinglan Zhao |
| author_sort | Na Sang |
| collection | DOAJ |
| description | Abstract Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell‐derived and patient‐derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage‐inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co‐administration of ZY0511 and DTP3, which specifically enhanced the pro‐apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC. |
| first_indexed | 2024-03-13T05:07:04Z |
| format | Article |
| id | doaj.art-ab847cd559a74dc58dab789332dfddab |
| institution | Directory Open Access Journal |
| issn | 2688-2663 |
| language | English |
| last_indexed | 2024-03-13T05:07:04Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj.art-ab847cd559a74dc58dab789332dfddab2023-06-16T09:40:37ZengWileyMedComm2688-26632023-06-0143n/an/a10.1002/mco2.269Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45BNa Sang0Xi Zhong1Kun Gou2Huan Liu3Jing Xu4Yang Zhou5Xia Zhou6Yuanzhi Liu7Zhiqian Chen8Yue Zhou9Yan Li10Lei Tao11Na Su12Lingyun Zhou13Jiahao Qiu14Xinyu Yang15Zeping Zuo16Li Fu17Jingyao Zhang18Dan Li19Cong Li20Qingxiang Sun21Jian Lei22Rui Li23Shengyong Yang24Xiaobo Cen25Yinglan Zhao26Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Pharmacology Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Pharmacology Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Pharmacology Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Pharmacy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaCenter of Infectious Diseases West China Hospital Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Pharmacology Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant‐Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaCore Facility Center West China Hospital Sichuan University Chengdu ChinaCore Facility Center West China Hospital Sichuan University Chengdu ChinaCore Facility Center West China Hospital Sichuan University Chengdu ChinaCore Facility Center West China Hospital Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaNational Chengdu Center for Safety Evaluation of Drugs State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu ChinaDepartment of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital, West China Medical School, Sichuan University Chengdu ChinaAbstract Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell‐derived and patient‐derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage‐inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co‐administration of ZY0511 and DTP3, which specifically enhanced the pro‐apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.https://doi.org/10.1002/mco2.269drug combinationGADD45Bhepatocellular carcinomaLSD1 inhibitor |
| spellingShingle | Na Sang Xi Zhong Kun Gou Huan Liu Jing Xu Yang Zhou Xia Zhou Yuanzhi Liu Zhiqian Chen Yue Zhou Yan Li Lei Tao Na Su Lingyun Zhou Jiahao Qiu Xinyu Yang Zeping Zuo Li Fu Jingyao Zhang Dan Li Cong Li Qingxiang Sun Jian Lei Rui Li Shengyong Yang Xiaobo Cen Yinglan Zhao Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B MedComm drug combination GADD45B hepatocellular carcinoma LSD1 inhibitor |
| title | Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B |
| title_full | Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B |
| title_fullStr | Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B |
| title_full_unstemmed | Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B |
| title_short | Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B |
| title_sort | pharmacological inhibition of lsd1 suppresses growth of hepatocellular carcinoma by inducing gadd45b |
| topic | drug combination GADD45B hepatocellular carcinoma LSD1 inhibitor |
| url | https://doi.org/10.1002/mco2.269 |
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