HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer

Zhang, Zhiyuan; He, Guodong; Lv, Yang; Liu, Yü; Niu, Zhihong; Feng, Qi Sheng; Hu, Ronggui; Xu, Jiacheng

doi:10.1038/s41419-022-04511-7

Cited by 23 publications

(33 citation statements)

References 32 publications

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“…The plasmids including pcDNA3.0-RPL23A-Flag and relevant point mutants, pcDNA3.0-p21-Flag, pcDNA3.0-RPL23A-Myc, pcDNA3.0-RPL23A-6His, pET22b-RPL23A-6His, and pET28A-His-RPL23A were built in our laboratory. Construction of some other plasmids and transfection of the plasmids are available in our previous published work 7 .…”

Section: Methodsmentioning

confidence: 99%

“…Overexpression lentivirus targeting HERC3 and RPL23A were built in GeneChem, Shanghai based on the relevant NCBI reference (reference of HERC3: NM_014606, reference of RPL23A: NM_000984), shHERC3 shRPL23A lentivirus and relevant control lentivirus were also constructed in GeneChem, Shanghai, and cells were infected following the instructions. The shRNA sequences of HERC3 and control could be found in our previous work 7 . The shRNA sequences of RPL23A were set as: shRPL23A: 5'-GAAGCTGTATGACATTGAT-3'.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous work, we used 2 steps differential analysis to identify the key E3 in CRC 7 . However, it cannot reflect the initiation and progression process of CRC which disturbs normal individual to cancer patients.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we identified that HERC3 was gradually reduced from colorectal tissues in healthy individuals to adjacent-tumors normal tissue in CRC patients, and to tumor tissues. We previously identified HERC3 to inhibit the metastasis via ubiquitination degradation EIF5A2 in CRC 7 . Nevertheless, the most important characteristics of tumorigenesis in normal individuals is still the uncontrolled cell proliferation, and the functions of HERC3 in CRC cell proliferation is still blank.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we discovered for the first time that HERC3 was associated with the tumor size, suppressed CRC cell growth and blocked the cell cycle at the G0-G1 phase. Besides, we previously discovered that EIF5A2 had almost non effect in regulating CRC cell proliferation and cell cycle indicating that HERC3 could control cell proliferation and cell cycle via other targets 7 . In this work, RPL23A was the first time to identified as the direct target of HERC3 to be responsible for the effects of HERC3 on cell cycle and cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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HERC3 directly targets RPL23A for ubiquitination degradation and further regulates Colorectal Cancer proliferation and the cell cycle

Zhang¹,

Wu²,

Fang³

et al. 2022

Int. J. Biol. Sci.

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Aims : Colorectal cancer (CRC) has high mortality and morbidity rates; however, the mechanism of CRC cells uncontrolled proliferation is unclarified, E3 ligases are widely reported to have crucial functions in cancers. HERC3 was once recognized as an important role in CRC, however its effects on CRC cell proliferation and cell cycle are blank. Methods : Correlation between HERC3 and clinical characteristics was analyzed. Coimmunoprecipitation, mass spectrometry analysis and GST-pull down were performed to identify interacting-proteins of HERC3. Expression pattern of RPL23A and its correlation between HERC3 was researched via qRT-PCR, western blot and immunohistochemistry. In vivo and vitro gain-and loss-of-function assays and rescue experiments concentrating HERC3-RPL23A axis in terms of cell proliferation and cell cycle were conducted. The ubiquitination regulatory mechanism between HERC3 and RPL23A were identified via vivo ubiquitylation assays, cycloheximide analysis and mass spectrometry analysis. GSEA aided to research the potential functional mechanism of RPL23A and validated by western blot and in vivo ubiquitylation assays. Results : HERC3 expression decreased gradually from colorectal tissues in healthy individuals to adjacent-tumors normal tissue in CRC patients, and to tumor tissues and HERC3 could inhibit CRC cell proliferation and arrest cells in the G0-G1 phase. RPL23A which was recognized as one potential target of HERC3 was identified to be overexpressed in CRC and could serve as a prognostic biomarker in CRC. RPL23A could also independently regulate the cell cycle and cell proliferation and attenuate the influence of HERC3 on CRC. In addition, HERC3 directly interacted with RPL23A and served as an E3 ligase to ubiquitination degrade RPL23A via K48-dependant manner through the HECT domain. Furthermore, HERC3 could regulate the ubiquitination of p21 and further modulate protein expression of c-Myc and p21 via regulating RPL23A. Conclusion : HERC3 controlled CRC proliferation, the cell cycle and regulated the c-Myc/p21 axis via directly targeting RPL23A for ubiquitination degradation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

HERC3 directly targets RPL23A for ubiquitination degradation and further regulates Colorectal Cancer proliferation and the cell cycle

Zhang¹,

Wu²,

Fang³

et al. 2022

Int. J. Biol. Sci.

Self Cite

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DHPS‐Mediated Hypusination Regulates METTL3 Self‐m6A‐Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors

Guo,

Ma,

Zhao

et al. 2024

Advanced Science

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Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi‐omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure‐based design, synthesis, and activity screening yielded the hit compound GL‐1 as a DHPS inhibitor. Notably, GL‐1 directly inhibits DHPS binding to eIF5A, whereas GC‐7 cannot. Based on the clarification of the mode of action of GL‐1 on DHPS, it is found that GL‐1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL‐1 inhibits the expression of several cytokines. GL‐1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL‐1 for clinical melanoma therapy.

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The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

Rong,

Zheng,

Chen

et al. 2024

J Cancer Res Clin Oncol

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Ubiquitination, a highly adaptable post-translational modification, plays a pivotal role in maintaining cellular protein homeostasis, encompassing cancer chemoresistance-associated proteins. Recent findings have indicated a potential correlation between perturbations in the ubiquitination process and the emergence of drug resistance in CRC cancer. Consequently, numerous studies have spurred the advancement of compounds specifically designed to target ubiquitinates, offering promising prospects for cancer therapy. In this review, we highlight the role of ubiquitination enzymes associated with chemoresistance to chemotherapy via the Wnt/β-catenin signaling pathway, epithelial–mesenchymal transition (EMT), and cell cycle perturbation. In addition, we summarize the application and role of small compounds that target ubiquitination enzymes for CRC treatment, along with the significance of targeting ubiquitination enzymes as potential cancer therapies.

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HERC3 regulates epithelial-mesenchymal transition by directly ubiquitination degradation EIF5A2 and inhibits metastasis of colorectal cancer

Cited by 23 publications

References 32 publications

HERC3 directly targets RPL23A for ubiquitination degradation and further regulates Colorectal Cancer proliferation and the cell cycle

HERC3 directly targets RPL23A for ubiquitination degradation and further regulates Colorectal Cancer proliferation and the cell cycle

DHPS‐Mediated Hypusination Regulates METTL3 Self‐m6A‐Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors

The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer

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