Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice
Summary: Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-07-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723008239 |
| _version_ | 1797779995166244864 |
|---|---|
| author | Xiao-Tong Lin Jie Zhang Ze-Yu Liu Di Wu Lei Fang Chun-Ming Li Hong-Qiang Yu Chuan-Ming Xie |
| author_facet | Xiao-Tong Lin Jie Zhang Ze-Yu Liu Di Wu Lei Fang Chun-Ming Li Hong-Qiang Yu Chuan-Ming Xie |
| author_sort | Xiao-Tong Lin |
| collection | DOAJ |
| description | Summary: Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, leading to upregulation of the canonical and noncanonical NF-κB pathways, and increases PD-L1 and AR-VRK2 expression, followed by induction of immune evasion, HCC tumorigenesis, and metastasis. Notably, the GAPDH inhibitor koningic acid (KA) activates immune response and protects against FBXW10-driven HCC in vivo. In HCC clinical samples, the expression of active GAPDH is positively correlated with that of FBXW10 and VRK2. We propose that the FBXW10/AR/VRK2/GAPDH/NF-κB axis is critical for HCC tumorigenesis in males. Targeting this axis with KA is a potential therapeutic strategy for male HCC patients. |
| first_indexed | 2024-03-12T23:38:23Z |
| format | Article |
| id | doaj.art-0992248c1e2047dd80432990e087a50f |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T23:38:23Z |
| publishDate | 2023-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0992248c1e2047dd80432990e087a50f2023-07-15T04:28:37ZengElsevierCell Reports2211-12472023-07-01427112812Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic miceXiao-Tong Lin0Jie Zhang1Ze-Yu Liu2Di Wu3Lei Fang4Chun-Ming Li5Hong-Qiang Yu6Chuan-Ming Xie7Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Corresponding authorSummary: Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men, but the underlying mechanism remains to be further explored. Here, we report that ubiquitinated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is responsible for HCC tumorigenesis in males. Mechanistically, FBXW10 promotes GAPDH polyubiquitination and activation; VRK2-dependent phosphorylation of GAPDH Ser151 residue is critical for GAPDH ubiquitination and activation. Activated GAPDH interacts with TRAF2, leading to upregulation of the canonical and noncanonical NF-κB pathways, and increases PD-L1 and AR-VRK2 expression, followed by induction of immune evasion, HCC tumorigenesis, and metastasis. Notably, the GAPDH inhibitor koningic acid (KA) activates immune response and protects against FBXW10-driven HCC in vivo. In HCC clinical samples, the expression of active GAPDH is positively correlated with that of FBXW10 and VRK2. We propose that the FBXW10/AR/VRK2/GAPDH/NF-κB axis is critical for HCC tumorigenesis in males. Targeting this axis with KA is a potential therapeutic strategy for male HCC patients.http://www.sciencedirect.com/science/article/pii/S2211124723008239CP: CancerCP: Molecular biology |
| spellingShingle | Xiao-Tong Lin Jie Zhang Ze-Yu Liu Di Wu Lei Fang Chun-Ming Li Hong-Qiang Yu Chuan-Ming Xie Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice Cell Reports CP: Cancer CP: Molecular biology |
| title | Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice |
| title_full | Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice |
| title_fullStr | Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice |
| title_full_unstemmed | Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice |
| title_short | Elevated FBXW10 drives hepatocellular carcinoma tumorigenesis via AR-VRK2 phosphorylation-dependent GAPDH ubiquitination in male transgenic mice |
| title_sort | elevated fbxw10 drives hepatocellular carcinoma tumorigenesis via ar vrk2 phosphorylation dependent gapdh ubiquitination in male transgenic mice |
| topic | CP: Cancer CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723008239 |
| work_keys_str_mv | AT xiaotonglin elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT jiezhang elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT zeyuliu elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT diwu elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT leifang elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT chunmingli elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT hongqiangyu elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice AT chuanmingxie elevatedfbxw10driveshepatocellularcarcinomatumorigenesisviaarvrk2phosphorylationdependentgapdhubiquitinationinmaletransgenicmice |