The KBTBD6/7-DRD2 axis regulates pituitary adenoma sensitivity to dopamine agonist treatment

Liu, Yan Ting; Liu, Fang; Cao, Lei; Li, Xue; Gu, Wei; Zheng, Ye; Tang, Hao; Wang, Yu; Hong, Ying; Zhang, Yong; Xie, Wan Qun; Ren, Bo; Xiao, Zhuo; Nie, Ying Jie; Hu, Ronggui; Wu, Zhe Bao

doi:10.1007/s00401-020-02180-4

Cited by 22 publications

(16 citation statements)

References 63 publications

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“…5-Fu-induced apoptosis in CRC is significantly reduced by dasatinib by inhibiting Src activation 44 . TRAF6 depletion induces decitabine resistance in triple-negative breast cancer by blocking decitabine-induced DNA methyltransferase DEGs radiation 45 . Cyclosporin A is a powerful immunosuppressive agent that acts on T-lymphocytes and blocks effective T-cell receptor signaling 46 , 47 .…”

Section: Discussionmentioning

confidence: 99%

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

Yang

Niu

2022

Sci Rep

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Coronavirus disease 2019 (COVID-19) poses a serious threat to human health and life. The effective prevention and treatment of COVID-19 complications have become crucial to saving patients’ lives. During the phase of mass spread of the epidemic, a large number of patients with pulmonary fibrosis and lung cancers were inevitably infected with the SARS-CoV-2 virus. Lung cancers have the highest tumor morbidity and mortality rates worldwide, and pulmonary fibrosis itself is one of the complications of COVID-19. Idiopathic lung fibrosis (IPF) and various lung cancers (primary and metastatic) become risk factors for complications of COVID-19 and significantly increase mortality in patients. Therefore, we applied bioinformatics and systems biology approaches to identify molecular biomarkers and common pathways in COVID-19, IPF, colorectal cancer (CRC) lung metastasis, SCLC and NSCLC. We identified 79 DEGs between COVID-19, IPF, CRC lung metastasis, SCLC and NSCLC. Meanwhile, based on the transcriptome features of DSigDB and common DEGs, we identified 10 drug candidates. In this study, 79 DEGs are the common core genes of the 5 diseases. The 10 drugs were found to have positive effects in treating COVID-19 and lung cancer, potentially reducing the risk of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

Yang

Niu

2022

Sci Rep

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“…For example, CUL3-KBTBD7 has been shown to destabilize neurofibromin 1 (NF1) in glioblastoma cells, making it a potential therapeutic target for glioblastoma ( 55 ). The close homolog of KBTBD7, KBTBD6 (sharing ~90% sequence identity), can form a heterodimeric complex with KBTBD7 to ubiquitinate TIAM1 (T-lymphoma and metastasis gene 1) and DRD2 (dopamine receptor D2) ( 56 , 74 ). However, in contrast to KBTBD7, the role of KBTBD6 in the regulation of Vangl is very limited and no endogenous interaction between KBTBD6 and Vangl has been detected, indicating that KBTBD7 is the major regulator of Vangl proteins.…”

Section: Discussionmentioning

confidence: 99%

“…In glioblastoma cells, KBTBD7 destabilized NF1 tumor suppressor, suggesting that it has an oncogenic role in the pathogenesis of glioblastoma ( 55 ). Moreover, KBTBD7 was found to decrease pituitary tumor sensitivity to dopamine agonist treatment through DRD2 ( 74 ). However, our analysis of breast cancer datasets and our studies on breast cancer cells and xenograft models revealed that KBTBD7 had a suppressive role on breast cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7–mediated Vangl ubiquitination and endoplasmic reticulum–associated degradation

et al. 2021

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The four-pass transmembrane proteins Vangl1 and Vangl2 are dedicated core components of Wnt/planar cell polarity (Wnt/PCP) signaling that critically regulate polarized cell behaviors in many morphological and physiological processes. Here, we found that the abundance of Vangl proteins is tightly controlled by the ubiquitin-proteasome system through endoplasmic reticulum–associated degradation (ERAD). The key ERAD component p97/VCP directly binds to Vangl at a highly conserved VCP-interacting motif and recruits the E3 ligase KBTBD7 via its UBA-UBX adaptors to promote Vangl ubiquitination and ERAD. We found that Wnt5a/CK1 prevents Vangl ubiquitination and ERAD by inducing Vangl phosphorylation, which facilitates Vangl export from the ER to the plasma membrane. We also provide in vivo evidence that KBTBD7 regulates convergent extension during zebrafish gastrulation and functions as a tumor suppressor in breast cancer by promoting Vangl degradation. Our findings reveal a previously unknown regulatory mechanism of Wnt/PCP signaling through the p97/VCP-KBTBD7–mediated ERAD pathway.

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“…However, these tumors are rarely reported, and the underlying mechanism is still unknown. To date, major studies have surmised that the resistance of prolactinoma to DAs may be due to the decrease in dopamine 2 receptor (DRD2) expression in tumor cells (5).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Temozolomide Treatment of Refractory Prolactinoma Resistant to Dopamine Agonists

et al. 2021

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Therapeutic agents for refractory prolactinomas that are resistant to dopamine agonists (DAs) are troublesome, and surgery often only removes a large part of the tumor without complete remission. Among the various second-line treatment regimens, the treatment effect of the alkylating agent temozolomide (TMZ) is only effective for approximately half of patients; however, complete remission is rare. Here we report a patient with prolactinoma who was resistant to high-dose cabergoline (CAB) treatment, demonstrating a continuous increase in both the tumor volume and the prolactin (PRL) level. Given that this case is a refractory prolactinoma, the patient underwent two transsphenoidal approach (TSA) surgeries. The pathological analysis indicated that the Ki-67 index increased significantly from 3% to 30%, and the expression levels of DRD2 and MGMT were low. Finally, TMZ treatment was recommended. A total of six cycles of TMZ standard chemotherapy shrank the tumor volume and the tumor disappeared completely. During the 6-month follow-up period, the tumor did not relapse again, and the PRL level was also normal. RNA sequencing and DNA whole genome sequencing were performed on this prolactinoma specimen, revealing 16 possible gene mutations, including a missense mutation of the PABPC1 gene. Additionally, the copy number variation analysis results showed that several chromosomes had copy number gains compared to the matched peripheral blood sample. In this case, low expression of DRD2 and high proliferation led to resistance to CAB, whereas low MGMT expression contributed to sensitivity to TMZ treatment. The results of genome sequencing still need further investigation at the molecular level to explain the tumor aggressiveness and high sensitivity to TMZ.

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The KBTBD6/7-DRD2 axis regulates pituitary adenoma sensitivity to dopamine agonist treatment

Cited by 22 publications

References 63 publications

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review

Regulation of Wnt/PCP signaling through p97/VCP-KBTBD7–mediated Vangl ubiquitination and endoplasmic reticulum–associated degradation

Case Report: Temozolomide Treatment of Refractory Prolactinoma Resistant to Dopamine Agonists

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