Inhibitor of Differentiation 4 (ID4) Inactivation Promotes De Novo Steroidogenesis and Castration-Resistant Prostate Cancer

Patel, Divya; Knowell, Ashley Evans; Korang-Yeboah, Maxwell; Sharma, Pankaj; Joshi, Jugal; Glymph, Shanora; Chinaranagari, Swathi; Nagappan, Peri; Palaniappan, Ravichandran; Bowen, Nathan J.; Chaudhary, Jaideep

doi:10.1210/me.2014-1100

Cited by 17 publications

(32 citation statements)

References 49 publications

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“…ID4 expression is generally down-regulated in prostate cancer 26,51,65 and regulates androgen sensitivity 50 whereas increased ID1 expression results in androgen insensitivity 66 , a hall mark of advanced disease with poor prognosis. Genetic ablation of ID4 in prostate cancer cells results in androgen insensitivity and promotes tumor growth in castrated mouse xenograft models 50 . Thus ID4 expression and function is highly relevant in cancer initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity

2015

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The four known ID proteins (ID1-4, Inhibitor of Differentiation) share a homologous helix loop helix (HLH) domain and act as dominant negative regulators of basic-HLH transcription factors. ID proteins also interact with many non-bHLH proteins in complex networks. The expression of ID proteins is increasingly observed in many cancers. Whereas ID-1, ID-2 and ID-3, are generally considered as tumor promoters, ID4 on the contrary has emerged as a tumor suppressor. In this study we demonstrate that ID4 heterodimerizes with ID-1, -2 and -3 and promote bHLH DNA binding, essentially acting as an inhibitor of inhibitors of differentiation proteins. Interaction of ID4 was observed with ID1, ID2 and ID3 that was dependent on intact HLH domain of ID4. Interaction with bHLH protein E47 required almost 3 fold higher concentration of ID4 as compared to ID1. Furthermore, inhibition of E47 DNA binding by ID1 was restored by ID4 in an EMSA binding assay. ID4 and ID1 were also colocalized in prostate cancer cell line LNCaP. The alpha helix forming alanine stretch N-terminal, unique to HLH ID4 domain was required for optimum interaction. Ectopic expression of ID4 in DU145 prostate cancer line promoted E47 dependent expression of CDKNI p21. Thus counteracting the biological activities of ID-1, -2 and -3 by forming inactive heterodimers appears to be a novel mechanism of action of ID4. These results could have far reaching consequences in developing strategies to target ID proteins for cancer therapy and understanding biologically relevant ID- interactions.

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Section: Discussionmentioning

confidence: 99%

“…All cells were cultured at 37°C and 5% CO2. DU145 cells over-expressing full length human ID4 (DU145+ID4) is described elsewhere 49,50 .…”

Section: Methodsmentioning

confidence: 99%

Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity

2015

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“…Silencing of ID4 in LNCaP prostate cancer cells (LNCaP(-)ID4) results in a castration resistant phenotype, partly due to gain of de novo steroidogenesis [72]. The LNCaP(-)ID4 cells also form tumors in castrated mice as compared to LNCaP cells [72] suggesting that ID4 is required to maintain the tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR.…”

Section: Id4 and Cancermentioning

confidence: 99%

“…The LNCaP(-)ID4 cells also form tumors in castrated mice as compared to LNCaP cells [72] suggesting that ID4 is required to maintain the tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR. These results could explain the Id4-/- mice prostate phenotype where AR is expressed at levels similar to wild type mice but associated with PIN lesions [23].…”

Section: Id4 and Cancermentioning

confidence: 99%

Inhibitor of differentiation 4 (ID4): From development to cancer

Patel

Morton

Carey

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Highly conserved Inhibitor of DNA Binding (ID1-4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, 2 and 3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, 2 and 3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, 2 and 3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promotes stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.

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“…The ID4 gene that is frequently silenced by hypermethylation (13,14) is indeed hypermethylated in parental MCF7 cells, suggesting that this silencing affects lumen formation, a critical pathway in maintaining the normal differentiated state of mammary epithelial cells. The fact that introduction of CEACAM1 into MCF7 cells that have lost the ability to express CEACAM1, restores ID4 expression suggests a direct link between CEACAM1 expression and relief of the gene silencing of ID4.…”

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Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

Shively

2016

Journal of Biological Chemistry

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Concomitant loss of lumen formation and cell adhesion protein CEACAM1 is a hallmark feature of breast cancer. In a threedimensional culture model, transfection of CEACAM1 into MCF7 breast cells can restore lumen formation by an unknown mechanism. ID4, a transcriptional regulator lacking a DNA binding domain, is highly up-regulated in CEACAM1-transfected MCF7 cells, and when down-regulated with RNAi, abrogates lumen formation. Conversely, when MCF7 cells, which fail to form lumena in a three-dimensional culture, are transfected with ID4, lumen formation is restored, demonstrating that ID4 may substitute for CEACAM1. After showing the ID4 promoter is hypermethylated in MCF7 cells but hypomethylated in MCF/ CEACAM1 cells, ID4 expression was induced in MCF7 cells by agents affecting chromatin remodeling and methylation. Mechanistically, CaMK2D was up-regulated in CEACAM1-transfected cells, effecting phosphorylation of HDAC4 and its sequestration in the cytoplasm by the adaptor protein 14-3-3. CaMK2D also phosphorylates CEACAM1 on its cytoplasmic domain and mutation of these phosphorylation sites abrogates lumen formation. Thus, CEACAM1 is able to maintain the active transcription of ID4 by an epigenetic mechanism involving HDAC4 and CaMK2D, and the same kinase enables lumen formation by CEACAM1. Because ID4 can replace CEACAM1 in parental MCF7 cells, it must act downstream from CEACAM1 by inhibiting the activity of other transcription factors that would otherwise prevent lumen formation. This overall mechanism may be operative in other cancers, such as colon and prostate, where the down-regulation of CEACAM1 is observed.Lumen formation, a central feature of mammary morphogenesis, is lost during mammary tumorigenesis, starting with filling in the lumen with cancer cells in ductal carcinoma in situ (1) and becoming more evident in invasive solid tumors (2). Identification of the molecules that change during this process and the underlying mechanisms causing these changes are major goals of breast cancer research. Among the many molecules identified so far, CEACAM1 stands out as a luminal expressed protein that is rapidly down-regulated in both ductal carcinoma in situ (3) and invasive breast cancer (2). Not surprisingly, luminal expression of CEACAM1 occurs throughout ductal tissues such as the liver, digestive and urogenital tract, and prostate, and its loss upon malignant transformation is one of the earliest events observed (4). To study its role in lumen formation, we originally placed MCF10F, a cell line that expresses CEACAM1, in a three-dimensional culture system pioneered by Bissell and co-workers (5), and observed lumen formation with CEACAM1 at the luminal surface (3). When its expression was blocked by antisense, anti-CEACAM1 antibody, or peptides derived from the N terminus of CEACAM1, lumen formation was abrogated, demonstrating that its expression played a central role in the complex process of lumenogenesis (3). As a next step, we demonstrated that MCF7 breast cancer cells that fail to express CEACAM1 o...

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Inhibitor of Differentiation 4 (ID4) Inactivation Promotes De Novo Steroidogenesis and Castration-Resistant Prostate Cancer

Cited by 17 publications

References 49 publications

Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity

Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity

Inhibitor of differentiation 4 (ID4): From development to cancer

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

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