DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

Feng, Jiaxuan; Wang, Jianpeng; Liu, Qian; Li, Jiye; Zhang, Qi; Zhuang, Zhengping; Yao, Xiaohui; Liu, Chunhui; Li, Yangfang; Cao, Lei; Li, Chuzhong; Gong, Lei; Li, Dan; Zhang, Yazhou; Gao, Hua

doi:10.3389/fonc.2019.00809

Cited by 30 publications

(22 citation statements)

References 39 publications

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“…DAPT, an inhibitor of the γsecretase complex, indirectly inhibits the pathway of Notch, a key target of γ-secretase. A γ-secretase inhibitor prevents proteolytic cleavage of the Notch intracellular domain (NICD), which is necessary for the Notch signaling response when NICD translocate to the nucleus and affect transcription 24,25 .…”

Section: Resultsmentioning

confidence: 99%

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

et al. 2020

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Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.

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Section: Resultsmentioning

confidence: 99%

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

et al. 2020

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“…Microarray hybridization and RT-qPCR were performed as previously described [ 44 ]. The total RNA of 30 samples was extracted and purified using the Rneasy®Mini Kit (QiaGen, Hilden, Germany) following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of DLK1/MEG3 locus on chromosome 14q32.2 reveals the differentiation of pituitary neuroendocrine tumors

Chen

Gao

Liu

et al. 2020

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Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs. However, for a substantial proportion of PitNETs, the etiology is poorly understood. According to the transcription data of 172 patients, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph or lactotroph differentiation. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 significantly promoted the synthesis and secretion of GH/IGF-1 and inhibited cell proliferation. In addition, loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines, a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line. These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs, especially somatotroph adenomas, and provide potential molecular target data for patient stratification and treatment in the future.

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“…Microarray hybridization and qRT-PCR were performed as previously described [26]. The total RNA of 30 samples was extracted and puri ed using the Rneasy®Mini Kit (QiaGen, Hilden, Germany) following the manufacturer's instructions.…”

Section: Reverse Transcription and Quantitative Pcrmentioning

confidence: 99%

The DLK1/MEG3 Locus is Related to the Differentiation of Pituitary Neuroendocrine Tumors

Chen

Gao

Liu

et al. 2020

Preprint

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Background: Pituitary neuroendocrine tumors (PitNETs) represent the neoplastic proliferation of the anterior pituitary gland. Transcription factors play a key role in the differentiation of PitNETs according to the 2017 WHO classification of tumors of endocrine organs. However, for a substantial proportion of PitNETs, the etiology is poorly understood.Methods: To analyze the diversity genes and pathways based on transcriptomic data of 172 patients by transcriptome sequencing, difference, correlation, and enrichment analysis. The transcriptomic data and clinical characteristics are applied to find the clinical significance of key genes by correlation analysis and ROC curve. Series functional experiments demonstrated the role of DLK1/MEG3 locus through antibody blocking and RNA interference in GH3, MMQ and ATT20 cell line.Results: In this study, we found the imprinting disorders of the 14q32.2 region and DLK1/MEG3 locus associated with the differentiation of PitNETs. As being specific feature change in somatotroph adenomas compared with other subtype adenomas, DLK1/MEG3 locus promoted somatotroph differentiation and inhibited tumor proliferation in PIT1(+) PitNET patients, furthermore, the level of DLK1 played a critical role in the trend of somatotroph differentiation or lactotroph differentiation in PIT1(+) PitNET patients. Anti-DLK1 monoclonal antibody blockade or siMEG3 both indicated that the DLK1/MEG3 domain significantly induced the synthesis and secretion of growth hormone/insulin-like growth factor-1 (GH/IGF-1) and inhibited cell growth and colony formation and that the loss of DLK1 activated the mTOR signaling pathway in high DLK1-expressing and PIT1(+) GH3 cell lines. There was a mild effect in the low DLK1-expressing and PIT1(+) MMQ cell lines and no effect in the PIT1(-) ATT20 cell line, regardless of whether anti-DLK1 monoclonal antibody blockade or siMEG3 was used. Conclusions: These findings emphasize that expression at the DLK1/MEG3 locus plays a key role in the differentiation of PitNETs in patients depending on the level of PIT1. In addition, these findings provide potential molecular target data for patient stratification and treatment in the future.

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DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

Cited by 30 publications

References 39 publications

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

p53 destabilizing protein skews asymmetric division and enhances NOTCH activation to direct self-renewal of TICs

Functional characterization of DLK1/MEG3 locus on chromosome 14q32.2 reveals the differentiation of pituitary neuroendocrine tumors

The DLK1/MEG3 Locus is Related to the Differentiation of Pituitary Neuroendocrine Tumors

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