Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis
Abstract Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer‐related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analys...
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| Format: | Article |
| Language: | English |
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Wiley
2025-05-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202411368 |
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| author | Qinglin Zhang Yunxing Huang Yin Tong Kenneth Tsz Chun Ng Jiangwen Zhang |
| author_facet | Qinglin Zhang Yunxing Huang Yin Tong Kenneth Tsz Chun Ng Jiangwen Zhang |
| author_sort | Qinglin Zhang |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer‐related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analysis has identified the histone acetyltransferase complex subunit VPS72 as being associated with HCC, yet the precise molecular mechanisms through which VPS72 contributes to hepatocarcinogenesis remain poorly understood. Our analysis of extensive HCC patient cohorts identifies a significant proportion with VPS72 copy number gains, which are strongly linked to adverse prognostic outcomes. By integrating RNA‐Seq, ChIP‐Seq, ATAC‐seq, and experimental validation, we show that VPS72 overexpression activates mTORC1 signaling, subsequently promoting lipid synthesis and driving HCC progression. We further uncover that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1. This study elucidates a novel regulatory axis that links dysregulated lipid metabolism with HCC progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention. |
| format | Article |
| id | doaj-art-84f7cb51871541128e2819d33fe718e8 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-84f7cb51871541128e2819d33fe718e82025-08-20T02:34:43ZengWileyAdvanced Science2198-38442025-05-011220n/an/a10.1002/advs.202411368Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 AxisQinglin Zhang0Yunxing Huang1Yin Tong2Kenneth Tsz Chun Ng3Jiangwen Zhang4School of Biological Sciences The University of Hong Kong Hong Kong SAR 999077 ChinaSchool of Biological Sciences The University of Hong Kong Hong Kong SAR 999077 ChinaDepartment of Pathology School of Clinical Medicine The University of Hong Kong Queen Mary Hospital Pokfulam Hong Kong SAR 999077 ChinaSchool of Biological Sciences The University of Hong Kong Hong Kong SAR 999077 ChinaSchool of Biological Sciences The University of Hong Kong Hong Kong SAR 999077 ChinaAbstract Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer‐related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analysis has identified the histone acetyltransferase complex subunit VPS72 as being associated with HCC, yet the precise molecular mechanisms through which VPS72 contributes to hepatocarcinogenesis remain poorly understood. Our analysis of extensive HCC patient cohorts identifies a significant proportion with VPS72 copy number gains, which are strongly linked to adverse prognostic outcomes. By integrating RNA‐Seq, ChIP‐Seq, ATAC‐seq, and experimental validation, we show that VPS72 overexpression activates mTORC1 signaling, subsequently promoting lipid synthesis and driving HCC progression. We further uncover that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1. This study elucidates a novel regulatory axis that links dysregulated lipid metabolism with HCC progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention.https://doi.org/10.1002/advs.202411368epigenetics regulationlipid metabolismmTORC1 signaling |
| spellingShingle | Qinglin Zhang Yunxing Huang Yin Tong Kenneth Tsz Chun Ng Jiangwen Zhang Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis Advanced Science epigenetics regulation lipid metabolism mTORC1 signaling |
| title | Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis |
| title_full | Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis |
| title_fullStr | Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis |
| title_full_unstemmed | Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis |
| title_short | Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis |
| title_sort | copy number gains of vps72 drive de novo lipogenesis and hepatocarcinogenesis via atf3 mtorc1 srebp1 axis |
| topic | epigenetics regulation lipid metabolism mTORC1 signaling |
| url | https://doi.org/10.1002/advs.202411368 |
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