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JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling.

ABSTRACT: The overexpression of HER2 is associated with a malignant proliferation of breast cancer. In this study, we developed a non-cytotoxic JWA gene activating compound 1 (JAC1) to inhibit the proliferation of HER2-positive breast cancer cells in vitro and in vivo experimental models. JAC1 increased the ubiquitination of HER2 at the K716 site through the E3 ubiquitin ligase SMURF1 which was due to the decreased expression of NEDD4, the E3 ubiquitin ligase of SMURF1. In conclusion, JAC1 suppresses the proliferation of HER2-positive breast cancer cells through the JWA triggered HER2 ubiquitination signaling. JAC1 may serve as a potential therapeutic agent for HER2-positive breast cancer.

SUBMITTER: Ren Y

PROVIDER: S-EPMC8055679 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling.

Ren Yanlin Y Chen Dongyin D Zhai Zurong Z Chen Junjie J Li Aiping A Liang Yan Y Zhou Jianwei J

Cell death discovery 20210419 1

The overexpression of HER2 is associated with a malignant proliferation of breast cancer. In this study, we developed a non-cytotoxic JWA gene activating compound 1 (JAC1) to inhibit the proliferation of HER2-positive breast cancer cells in vitro and in vivo experimental models. JAC1 increased the ubiquitination of HER2 at the K716 site through the E3 ubiquitin ligase SMURF1 which was due to the decreased expression of NEDD4, the E3 ubiquitin ligase of SMURF1. In conclusion, JAC1 suppresses the ...[more]

PMID: 33875644

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Project description:BackgroundEstrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulators, such as tamoxifen. However, tamoxifen resistance is commonly observed by altered ER alpha signaling. Thus, further understanding of the molecular mechanisms, which regulates ER alpha signaling, is important to improve breast cancer therapy.MethodsSMURF1 and ER alpha protein expression levels were measured by western blot, while the ER alpha target genes were measured by real-time PCR. WST-1 assay was used to measure cell viability; the xeno-graft tumor model were used for in vivo study. RNA sequencing was analyzed by Ingenuity Pathway Analysis. Identification of ER alpha signaling was accomplished with luciferase assays, real-time RT-PCR and Western blotting. Protein stability assay and ubiquitin assay was used to detect ER alpha protein degradation. Immuno-precipitation based assays were used to detect the interaction domain between ER alpha and SMURF1. The ubiquitin-based Immuno-precipitation based assays were used to detect the specific ubiquitination manner happened on ER alpha.ResultsHere, we identify the E3 ligase SMURF1 facilitates ER alpha signaling. We show that depletion SMURF1 decreases ER alpha positive cell proliferation in vitro and in vivo. SMURF1 depletion based RNA-sequence data shows SMURF1 is necessary for ER alpha target gene expression in the transcriptomic scale. Immunoprecipitation indicates that SMURF1 associates with the N-terminal of ER alpha in the cytoplasm via its HECT domain. SMURF1 increases ER alpha stability, possibly by inhibiting K48-specific poly-ubiquitination process on ER alpha protein. Interestingly, SMURF1 expression could be induced via estradiol treatment.ConclusionsOur study reveals a novel positive feedback between SMURF1 and ER alpha signaling in supporting breast cancer growth. Targeting SMURF1 could be one promising strategy for ER alpha positive breast cancer treatment.

Dataset Information

JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling.

Publications

JAC1 suppresses proliferation of breast cancer through the JWA/p38/SMURF1/HER2 signaling.

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