Inhibitor of DNA binding 2 is a novel therapeutic target for stemness of head and neck squamous cell carcinoma

Bae, Woo Jin; Koo, Bon Seok; Lee, Sang Hyuk; Kim, Jin Man; Rho, Young Soo; Lim, Jae Yol; Moon, Jung Hwa; Cho, Jae Hoon; Lim, Young Chang

doi:10.1038/bjc.2017.373

Cited by 11 publications

(9 citation statements)

References 37 publications

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“…In cancers, ID proteins are found at a higher level than in normal adult tissues where they function to sustain self-renewal of stem or stem-like cancer cells and inhibit apoptosis and entry of tumour cells into senescence [17, 18]. For ID2 it has been shown that expression is required to maintain glioma [40], glioblastoma [41], head and neck [42], and colorectal cancer stem/stem-like cells. Previously it has been demonstrated in normal mouse mammary cells and other non-transformed epithelial cell types that exposure to TGFβ resulted in decreased ID2 mRNA and protein levels, whereas BMP7 could both over-ride the TGFβ-mediated ID2 repression and, on its own, promote increased ID2 expression [29, 30, 43].…”

Section: Discussionmentioning

confidence: 99%

Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain

et al. 2019

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BackgroundDissemination of breast cancers to the brain is associated with poor patient outcome and limited therapeutic options. In this study we sought to identify novel regulators of brain metastasis by profiling mouse mammary carcinoma cells spontaneously metastasising from the primary tumour in an immunocompetent syngeneic host.Methods4T1 mouse mammary carcinoma sublines derived from primary tumours and spontaneous brain and lung metastases in BALB/c mice were subject to genome-wide expression profiling. Two differentially expressed genes, Id2 and Aldh3a1, were validated in in-vivo models using mouse and human cancer cell lines. Clinical relevance was investigated in datasets of breast cancer patients with regards to distant metastasis-free survival and brain metastasis relapse-free survival. The role of bone morphogenetic protein (BMP)7 in regulating Id2 expression and promoting cell survival was investigated in two-dimensional and three-dimensional in-vitro assays.ResultsIn the spontaneous metastasis model, expression of Id2 and Aldh3a1 was significantly higher in 4T1 brain-derived sublines compared with sublines from lung metastases or primary tumour. Downregulation of expression impairs the ability of cells to colonise the brain parenchyma whereas ectopic expression in 4T1 and human MDA-MB-231 cells promotes dissemination to the brain following intracardiac inoculation but has no impact on the efficiency of lung colonisation. Both genes are highly expressed in oestrogen receptor (ER)-negative breast cancers and, within this poor prognosis sub-group, increased expression correlates with reduced distant metastasis-free survival. ID2 expression also associates with reduced brain metastasis relapse-free survival. Mechanistically, BMP7, which is present at significantly higher levels in brain tissue compared with the lungs, upregulates ID2 expression and, after BMP7 withdrawal, this elevated expression is retained. Finally, we demonstrate that either ectopic expression of ID2 or BMP7-induced ID2 expression protects tumour cells from anoikis.ConclusionsThis study identifies ID2 as a key regulator of breast cancer metastasis to the brain. Our data support a model in which breast cancer cells that have disseminated to the brain upregulate ID2 expression in response to astrocyte-secreted BMP7 and this serves to support metastatic expansion. Moreover, elevated ID2 expression identifies breast cancer patients at increased risk of developing metastatic relapse in the brain.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1093-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain

et al. 2019

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“…Furthermore, ectopic miR-29c expression sensitizes cancer cells to paclitaxel chemotherapy [ 51 ]. Similarly, ID2 expression in cancer is also correlated with self-renewal ability and resistance to chemotherapy [ 52 , 53 ], suggesting the significance of miR-29c and ID2 axis in cancer. Our findings suggest that downregulation of IPW-miR-29c axis is critical for the maintenance of CSC in DCIS, which emphasizes the importance of IPW-miR-29c in early carcinogenesis and its progression.…”

Section: Discussionmentioning

confidence: 99%

LncRNA IPW inhibits growth of ductal carcinoma in situ by downregulating ID2 through miR-29c

Deshpande

Sharma²,

Yin

et al. 2022

Breast Cancer Res

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Background Ductal carcinoma in situ (DCIS) of breast is the noninvasive lesion that has propensity to progress to the malignant form. At present, it is still unknown which lesions can potentially progress to invasive forms. In this study, we aimed to identify key lncRNAs involved in DCIS growth. Methods We employ disease-related lncProfiler array to identify IPW in specimens of DCIS and matching control samples and validate the observations in three DCIS-non-tumorigenic cell lines. Further, we examine the mechanism of IPW action and the downstream signaling in in vitro and in vivo assays. Importantly, we screened a library containing 390 natural compounds to identify candidate compound selectively inhibiting IPW low DCIS cells. Results We identified lncRNA IPW as a novel tumor suppressor critical for inhibiting DCIS growth. Ectopic expression of IPW in DCIS cells strongly inhibited cell proliferation, colony formation and cell cycle progression while silencing IPW in primary breast cells promoted their growth. Additionally, orthotropic implantation of cells with ectopic expression of IPW exhibited decreased tumor growth in vivo. Mechanistically, IPW epigenetically enhanced miR-29c expression by promoting H3K4me3 enrichment in its promoter region. Furthermore, we identified that miR-29c negatively regulated a stemness promoting gene, ID2, and diminished self-renewal ability of DCIS cells. Importantly, we screened a library containing 390 natural compounds and identified toyocamycin as a compound that selectively inhibited the growth of DCIS with low expression of IPW, while it did not affect DCIS with high IPW expression. Toyocamycin also suppressed genes associated with self-renewal ability and inhibited DCIS growth in vivo. Conclusion Our findings revealed a critical role of the IPW-miR-29c-ID2 axis in DCIS formation and suggested potential clinical use of toyocamycin for the treatment of DCIS.

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“…Wen et al (12) revealed that ID2 upregulated notch3 expression via blocking the binding of E2A to an E-box motif in the notch3 promoter; further decreased expression of ID2 was associated with worse long-term metastasis-free survival in patients with breast cancer (12). Moreover, Bae et al (29) revealed that ID2 expression was significantly higher in the head and neck squamous cell carcinoma (HNSCC) cells with stemness, compared with that in differentiated HNSCC cells; furthermore, increased expression of ID2 was closely associated with poorer post-treatment survival rates in patients with HNSCC. By contrast, it was observed in the current study that increased expression of ID2 was strongly associated with better survival outcomes in patients with LUAD.…”

Section: Discussionmentioning

confidence: 99%

Prognostic effects of the expression of inhibitor of DNA‑binding family members on patients with lung adenocarcinoma

et al. 2020

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The basic helix-loop-helix (bHLH) transcription factors are negatively regulated by inhibitor of DNA-binding (ID) proteins. Several studies have demonstrated that ID family proteins are dysregulated in a variety of cancer types, including in lung adenocarcinoma (LUAD). In current study, the prognostic value of ID family members was evaluated by investigating publicly accessible databases, including Oncomine, Kaplan-Meier plotter, UALCAN and the Human Protein Atlas. It was observed that the mRNA expression of all ID members was downregulated in LUAD tumor tissues compared with those in normal tissues according to the Oncomine and UALCAN databases. Additionally, increased mRNA expression levels of ID2 and ID1 were associated with improved and poorer survival time, respectively. Notably, ID3 and ID4 expression was not associated with survival in patients with LUAD. At the protein level, high ID2 significantly predicted an improved survival outcome while high ID1 is associated with shorter survival time. Thus, the results indicate that the ID proteins, particularly ID2, exhibit significant prognostic value in LUAD. More studies are required to elucidate the underlying molecular mechanisms behind the role of the ID family in the development of LUAD.

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Inhibitor of DNA binding 2 is a novel therapeutic target for stemness of head and neck squamous cell carcinoma

Cited by 11 publications

References 37 publications

Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain

Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain

LncRNA IPW inhibits growth of ductal carcinoma in situ by downregulating ID2 through miR-29c

Prognostic effects of the expression of inhibitor of DNA‑binding family members on patients with lung adenocarcinoma

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