HRD1 promotes non-small cell lung carcinoma metastasis by blocking autophagy-mediated MIEN1 degradation

Zeng, Cheng; Guo, Jing; Wu, Jiajia; Che, Tiantian; Huang, Xiaoping; Liu, Huawen; Lin, Zhenghong

doi:10.1016/j.jbc.2023.104723

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…In contrast to its tumor-suppressive activity, SYVN1 exerts tumor-promoting effects through ubiquitination and degradation of tumor-suppressors in different cancers, including colon cancer [ 11 ], prostate cancer [ 3 ], lung cancer [ 2 ], and hepatocellular carcinoma [ 8 ]. SYVN1 promotes non-small cell lung cancer metastasis by blocking autophagy-mediated MIEN1 degradation [ 15 ]. However, the molecular mechanism of SYVN1 in cancer progression is not fully clarified.…”

Section: Discussionmentioning

confidence: 99%

SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1

Duan,

Kong,

Jiang

et al. 2024

Cell Div

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E3 ubiquitin ligase synoviolin (SYVN1) has been reported to participate in many human cancers. This study aimed to investigate SYVN1’s roles and molecular pathways in papillary thyroid cancer (PTC). The functions of SYVN1 in PTC were further analyzed using gain- and loss-of-function methods and numerous investigations in cellular function and molecular biology. The findings demonstrated that the overexpression of SYVN1 markedly suppressed the proliferation, migration, and invasion of PTC cell lines (NPA87 and TPC-1). We found that SYVN1 interacted with HMGB1 and promoted its ubiquitination and degradation. In addition, SYVN1 effectively impairs cell proliferation, migration, invasion, and the formation of tumor xenografts in mice models. However, this effect may be partly reversed by overexpressing HMGB1. Thus, SYVN1 may inhibit the proliferation, migration, and invasion of PTC cells by disrupting HMGB1. Consequently, SYVN1 might be considered a promising therapeutic target for PTC.

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Section: Discussionmentioning

confidence: 99%

SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1

Duan,

Kong,

Jiang

et al. 2024

Cell Div

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“…With regards to SYVN1, previous studies have shown that it functions as a tumor suppressor in breast ( 37 , 39 , 41 , 76 , 77 ) and ovarian ( 40 ) cancers. On the contrary, the tumor-promoting (oncogenic) effects of SYVN1 have been revealed in colon cancer ( 78 ), lung cancer ( 79 , 80 ), and hepatocellular carcinoma ( 81 , 82 ).…”

Section: Discussionmentioning

confidence: 99%

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics

Liu,

Chen,

et al. 2024

Cancer Letters

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HRD1 promotes non-small cell lung carcinoma metastasis by blocking autophagy-mediated MIEN1 degradation

Cited by 3 publications

References 52 publications

SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1

SYVN1 modulates papillary thyroid carcinoma progression by destabilizing HMGB1

VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Autophagy flux in bladder cancer: Cell death crosstalk, drug and nanotherapeutics

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