Increased expression of Id1 and Id3 promotes tumorigenicity by enhancing angiogenesis and suppressing apoptosis in small cell lung cancer

Chen, Danqing; Forootan, Shiva S.; Gosney, John R.; Forootan, Farzad Seyed; Ke, Youqiang

doi:10.18632/genesandcancer.20

Cited by 26 publications

(15 citation statements)

References 44 publications

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“…High ID1/ID3 expression in ILC tumors was associated with downregulation of cell cycle-related genes, which is in contrast to the proliferative effects of ID1 and ID3 in anchorage-independent conditions, and with upregulation of pathways associated with angiogenesis and the matrisome. While these results are based on correlation analyses, they are largely consistent with previous reports in other contexts 27 , 31 , 44 , 56 and should be validated in further functional studies. Taken together, these data suggest that ID1 and ID3 may play roles in multiple stages of tumor growth and metastasis by regulating different processes in attached versus detached cancer cells.…”

Section: Discussionsupporting

confidence: 90%

“…ID1 and ID3 have previously been characterized as part of a common murine and human lung metastatic signature in triple negative breast cancer cells 28 , 29 and extensively validated as regulators of metastasis 27 , 28 , 30 . ID1 and ID3 have also been implicated in anchorage-independent growth in soft agar in small cell lung cancer 31 ; however, they have not previously been studied in ILC. Through a series of functional in vitro experiments using cell lines and in silico analyses of patient tumors, herein we have discovered a role for ID1 and ID3 as novel drivers and potential therapeutic targets for ILC.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Tasdemir

Ding

Savariau

et al. 2020

Sci Rep

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Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer with distinct molecular and clinical features from the more common subtype invasive ductal carcinoma (IDC). ILC cells exhibit anchorage-independent growth in ultra-low attachment (ULA) suspension cultures, which is largely attributed to the loss of E-cadherin. In addition to anoikis resistance, herein we show that human ILC cell lines exhibit enhanced cell proliferation in ULA cultures as compared to IDC cells. Proteomic comparison of ILC and IDC cell lines identified induction of PI3K/Akt and p90-RSK pathways specifically in ULA culture in ILC cells. Further transcriptional profiling uncovered unique upregulation of the inhibitors of differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished the anchorage-independent growth of ILC cell lines through cell cycle arrest. We find that ID1 and ID3 expression is higher in human ILC tumors as compared to IDC, correlated with worse prognosis uniquely in patients with ILC and associated with upregulation of angiogenesis and matrisome-related genes. Altogether, our comprehensive study of anchorage independence in human ILC cell lines provides mechanistic insights and clinical implications for metastatic dissemination of ILC and implicates ID1 and ID3 as novel drivers and therapeutic targets for lobular breast cancer.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Tasdemir

Ding

Savariau

et al. 2020

Sci Rep

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“…Surprisingly, genes in clusters 3 and 4 were associated with an unfavorable prognosis in glioma. For example, Annexin A2 ( ANXA2 ), Ferritin Light Chain ( FTL ), and Inhibitor of DNA-binding-1 ( ID1 ) fulfill important tumor functions in glioma and glioblastoma, such as the promotion of invasion and tumor progression 42 , proliferation 26 , or chemoresistance 43 – 45 . The fourth cluster included detrimental genes such as ALDH1A3 promoting stemness-like features in glioma, and is associated with worse survival 27 , 28 .…”

Section: Discussionmentioning

confidence: 99%

Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells

et al. 2020

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Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREBbinding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27Mmutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.

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“…In colon cancer HCT116 cells, ID1 inhibited apoptosis induced by chemotherapy drugs and ultraviolet light [27] . In small cell lung cancer, it has been reported that the high expression of ID1 can signi cantly inhibit the apoptosis of tumor cells [28] . Our study is highly in line with results of these former studies.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of ID1 mediates resistance to osimertinib in T790M positive non-small cell lung cancer through epithelial-mesenchymal transition

Liu¹,

Fang²,

Wu³

et al. 2020

Preprint

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Objective To analyzed the effect of ID1 overexpression on osimertinib resistance to T790M positive non-small cell lung cancer (NSCLC). Methods We established drug resistant cell line H1975/OR from osimertinib sensitive cell line H1975. Protein alterations of ID1 and Epithelial mesenchymal transition (EMT) were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA. ID1 silencing and overexpression was used to investigate the effect of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess proliferation rate of ID1 differently expressed cells. Cell cycle and apoptosis was compared using flow cytometry. Results In our study, we found that in osimertinib resistant NSCLC cells, the expression level of EMT related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin was higher than that of sensitive cells. ID1 expression level was closely related to E-cadherin and vimentin both in osimertinib sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression of H1975/OR cells could promote the apoptosis induced by osimertinib and block cell cycle at G1/G0 stage. Our study indicated that ID1 may induce EMT in T790M positive NSCLC, which mediates drug resistance of osimertinib. Conclusions Our study reveal the mechanism of ID1 mediated resistance to osimertinib in T790M positive NSCLC through EMT, which may provide new ideas and methods for treatment of EGFR mutated NSCLC after osimertinib resistance.

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Increased expression of Id1 and Id3 promotes tumorigenicity by enhancing angiogenesis and suppressing apoptosis in small cell lung cancer

Cited by 26 publications

References 44 publications

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells

Overexpression of ID1 mediates resistance to osimertinib in T790M positive non-small cell lung cancer through epithelial-mesenchymal transition

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