F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner
The roles of F-box protein 43 (FBXO43) in carcinogenesis have been rarely revealed. The present study investigates the expression, function, and underlying mechanism of FBXO43 in hepatocellular carcinoma (HCC). Firstly, the expression and clinical significance of FBXO43 in HCC were investigated bioi...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/3/957 |
| _version_ | 1797624977095131136 |
|---|---|
| author | Huijun Zhou Chong Zeng Jie Liu Haijun Luo Wei Huang |
| author_facet | Huijun Zhou Chong Zeng Jie Liu Haijun Luo Wei Huang |
| author_sort | Huijun Zhou |
| collection | DOAJ |
| description | The roles of F-box protein 43 (FBXO43) in carcinogenesis have been rarely revealed. The present study investigates the expression, function, and underlying mechanism of FBXO43 in hepatocellular carcinoma (HCC). Firstly, the expression and clinical significance of FBXO43 in HCC were investigated bioinformatically and experimentally using online omics data and local tissue samples. The role of N6-methyladenosine modification (m6A) of mRNA in regulating FBXO43 expression and the effects of m6A/FBXO43 axis alteration on cell proliferation and invasion were investigated further. Moreover, the underlying mechanism of the oncogenic FBXO43 was also explored. The results demonstrated that FBXO43 was significantly upregulated in HCC and was positively correlated with advanced progression and poor prognosis in patients. METTL3 and IGF2BP2 expressions were positively correlated with FBXO43 expression and served as the writer and reader of FBXO43 m6A, respectively, which stabilized and upregulated FBXO43 mRNA in HCC. FBXO43 silencing significantly reduced cell proliferation and invasion, and ectopic expression of FBXO43 could significantly restore the inhibitory effects caused by METTL3 and IGF2BP2 depletion in HCC cells. Mechanistically, FBXO43 depletion reduced the expression of UBE2C, a p53 ubiquitin-conjugating enzyme, suppressed proteasomal degradation of p53, and thus inhibited cell proliferation and invasion in HCC. In summary, the present study revealed that METTL3/IGF2BP2 mediated m6A contributed to the upregulation of FBXO43 that promoted the malignant progression of HCC by stimulating p53 degradation in a UBE2C-dependent manner, highlighting the promising application of FBXO43 as a target in HCC treatment. |
| first_indexed | 2024-03-11T09:50:18Z |
| format | Article |
| id | doaj.art-a5289cca176b468bac37fd064ba9ff78 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:50:18Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a5289cca176b468bac37fd064ba9ff782023-11-16T16:19:36ZengMDPI AGCancers2072-66942023-02-0115395710.3390/cancers15030957F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent MannerHuijun Zhou0Chong Zeng1Jie Liu2Haijun Luo3Wei Huang4Department of Gastroenterology and Urology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410083, ChinaDepartment of Medicine, The Seventh Affiliated Hospital, Hengyang Medical School, University of South China, Changsha 410004, ChinaDepartment of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, ChinaDepartment of Pathology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha 410004, ChinaDepartment of Oncology, Xiangya Hospital, Central South University, Changsha 410083, ChinaThe roles of F-box protein 43 (FBXO43) in carcinogenesis have been rarely revealed. The present study investigates the expression, function, and underlying mechanism of FBXO43 in hepatocellular carcinoma (HCC). Firstly, the expression and clinical significance of FBXO43 in HCC were investigated bioinformatically and experimentally using online omics data and local tissue samples. The role of N6-methyladenosine modification (m6A) of mRNA in regulating FBXO43 expression and the effects of m6A/FBXO43 axis alteration on cell proliferation and invasion were investigated further. Moreover, the underlying mechanism of the oncogenic FBXO43 was also explored. The results demonstrated that FBXO43 was significantly upregulated in HCC and was positively correlated with advanced progression and poor prognosis in patients. METTL3 and IGF2BP2 expressions were positively correlated with FBXO43 expression and served as the writer and reader of FBXO43 m6A, respectively, which stabilized and upregulated FBXO43 mRNA in HCC. FBXO43 silencing significantly reduced cell proliferation and invasion, and ectopic expression of FBXO43 could significantly restore the inhibitory effects caused by METTL3 and IGF2BP2 depletion in HCC cells. Mechanistically, FBXO43 depletion reduced the expression of UBE2C, a p53 ubiquitin-conjugating enzyme, suppressed proteasomal degradation of p53, and thus inhibited cell proliferation and invasion in HCC. In summary, the present study revealed that METTL3/IGF2BP2 mediated m6A contributed to the upregulation of FBXO43 that promoted the malignant progression of HCC by stimulating p53 degradation in a UBE2C-dependent manner, highlighting the promising application of FBXO43 as a target in HCC treatment.https://www.mdpi.com/2072-6694/15/3/957HCCFBXO43m6A modificationp53UBE2C |
| spellingShingle | Huijun Zhou Chong Zeng Jie Liu Haijun Luo Wei Huang F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner Cancers HCC FBXO43 m6A modification p53 UBE2C |
| title | F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner |
| title_full | F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner |
| title_fullStr | F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner |
| title_full_unstemmed | F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner |
| title_short | F-Box Protein 43, Stabilized by N6-Methyladenosine Methylation, Enhances Hepatocellular Carcinoma Cell Growth and Invasion via Promoting p53 Degradation in a Ubiquitin Conjugating Enzyme E2 C-Dependent Manner |
| title_sort | f box protein 43 stabilized by n6 methyladenosine methylation enhances hepatocellular carcinoma cell growth and invasion via promoting p53 degradation in a ubiquitin conjugating enzyme e2 c dependent manner |
| topic | HCC FBXO43 m6A modification p53 UBE2C |
| url | https://www.mdpi.com/2072-6694/15/3/957 |
| work_keys_str_mv | AT huijunzhou fboxprotein43stabilizedbyn6methyladenosinemethylationenhanceshepatocellularcarcinomacellgrowthandinvasionviapromotingp53degradationinaubiquitinconjugatingenzymee2cdependentmanner AT chongzeng fboxprotein43stabilizedbyn6methyladenosinemethylationenhanceshepatocellularcarcinomacellgrowthandinvasionviapromotingp53degradationinaubiquitinconjugatingenzymee2cdependentmanner AT jieliu fboxprotein43stabilizedbyn6methyladenosinemethylationenhanceshepatocellularcarcinomacellgrowthandinvasionviapromotingp53degradationinaubiquitinconjugatingenzymee2cdependentmanner AT haijunluo fboxprotein43stabilizedbyn6methyladenosinemethylationenhanceshepatocellularcarcinomacellgrowthandinvasionviapromotingp53degradationinaubiquitinconjugatingenzymee2cdependentmanner AT weihuang fboxprotein43stabilizedbyn6methyladenosinemethylationenhanceshepatocellularcarcinomacellgrowthandinvasionviapromotingp53degradationinaubiquitinconjugatingenzymee2cdependentmanner |