USP12 facilitates gastric cancer progression via stabilizing YAP
Abstract The dysregulation of Hippo signaling is a crucial factor driving the progression of gastric cancer, making the targeting of the Hippo pathway a promising therapeutic strategy. However, effective drugs targeting the Hippo/YAP axis remain unavailable. Thus, identifying potential therapeutic t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-01943-2 |
| _version_ | 1827284474343194624 |
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| author | Peng Zhang Dongyi Liu Yifeng Zang Jinqing Wang Ziping Liu Jian Zhu Xin Li Yinlu Ding |
| author_facet | Peng Zhang Dongyi Liu Yifeng Zang Jinqing Wang Ziping Liu Jian Zhu Xin Li Yinlu Ding |
| author_sort | Peng Zhang |
| collection | DOAJ |
| description | Abstract The dysregulation of Hippo signaling is a crucial factor driving the progression of gastric cancer, making the targeting of the Hippo pathway a promising therapeutic strategy. However, effective drugs targeting the Hippo/YAP axis remain unavailable. Thus, identifying potential therapeutic targets and mechanisms that inhibit the activity of the Hippo/YAP axis in gastric cancer is of paramount importance. The ubiquitination modification of the Hippo/YAP pathway plays a significant role in signaling transduction and cancer progression. In an effort to shed light on effective therapeutic targets, we conducted a screening using a deubiquitinase small interfering RNA library, leading to the identification of USP12 as an important deubiquitinase in the context of Hippo/YAP axis and the progression of gastric cancer. Our bioinformatic analysis further demonstrated a correlation between USP12 and poor survival, as well as a positive association with classical YAP target genes in gastric cancer samples. Notably, USP12 depletion was found to inhibit gastric cancer progression via the Hippo/YAP axis, whereas USP12 overexpression exhibited the opposite effect, promoting gastric cancer growth and enhancing YAP activity. Further studies through immuno-staining and immuno-precipitation assays indicated the nuclear localization of USP12 and its association with YAP to enhance YAP stability. Specifically, our findings revealed that USP12 could inhibit K48-linked poly-ubiquitination of YAP, predominantly at the K315 site. As a result, we have identified a novel regulatory mechanism involving USP12 and Hippo signaling in the progression of gastric cancer, with the potential for blockade of USP12 to materialize as a promising strategy for combating gastric cancer. |
| first_indexed | 2024-04-24T09:57:06Z |
| format | Article |
| id | doaj.art-e72d2febe88f48d480d2753058f9496b |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-24T09:57:06Z |
| publishDate | 2024-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-e72d2febe88f48d480d2753058f9496b2024-04-14T11:08:03ZengNature Publishing GroupCell Death Discovery2058-77162024-04-0110111310.1038/s41420-024-01943-2USP12 facilitates gastric cancer progression via stabilizing YAPPeng Zhang0Dongyi Liu1Yifeng Zang2Jinqing Wang3Ziping Liu4Jian Zhu5Xin Li6Yinlu Ding7Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Anaesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of General Surgery, Shengjing Hospital of China Medical UniversityXinxiang Key Laboratory of Tumor Migration and Invasion Precision Medicine, School of Medical Technology, Xinxiang Medical UniversityDepartment of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityAbstract The dysregulation of Hippo signaling is a crucial factor driving the progression of gastric cancer, making the targeting of the Hippo pathway a promising therapeutic strategy. However, effective drugs targeting the Hippo/YAP axis remain unavailable. Thus, identifying potential therapeutic targets and mechanisms that inhibit the activity of the Hippo/YAP axis in gastric cancer is of paramount importance. The ubiquitination modification of the Hippo/YAP pathway plays a significant role in signaling transduction and cancer progression. In an effort to shed light on effective therapeutic targets, we conducted a screening using a deubiquitinase small interfering RNA library, leading to the identification of USP12 as an important deubiquitinase in the context of Hippo/YAP axis and the progression of gastric cancer. Our bioinformatic analysis further demonstrated a correlation between USP12 and poor survival, as well as a positive association with classical YAP target genes in gastric cancer samples. Notably, USP12 depletion was found to inhibit gastric cancer progression via the Hippo/YAP axis, whereas USP12 overexpression exhibited the opposite effect, promoting gastric cancer growth and enhancing YAP activity. Further studies through immuno-staining and immuno-precipitation assays indicated the nuclear localization of USP12 and its association with YAP to enhance YAP stability. Specifically, our findings revealed that USP12 could inhibit K48-linked poly-ubiquitination of YAP, predominantly at the K315 site. As a result, we have identified a novel regulatory mechanism involving USP12 and Hippo signaling in the progression of gastric cancer, with the potential for blockade of USP12 to materialize as a promising strategy for combating gastric cancer.https://doi.org/10.1038/s41420-024-01943-2 |
| spellingShingle | Peng Zhang Dongyi Liu Yifeng Zang Jinqing Wang Ziping Liu Jian Zhu Xin Li Yinlu Ding USP12 facilitates gastric cancer progression via stabilizing YAP Cell Death Discovery |
| title | USP12 facilitates gastric cancer progression via stabilizing YAP |
| title_full | USP12 facilitates gastric cancer progression via stabilizing YAP |
| title_fullStr | USP12 facilitates gastric cancer progression via stabilizing YAP |
| title_full_unstemmed | USP12 facilitates gastric cancer progression via stabilizing YAP |
| title_short | USP12 facilitates gastric cancer progression via stabilizing YAP |
| title_sort | usp12 facilitates gastric cancer progression via stabilizing yap |
| url | https://doi.org/10.1038/s41420-024-01943-2 |
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