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

Choi, Hye Yeon; Siddique, Hifzur R.; Zheng, Mengmei; Kou, Yi; Yeh, Da‐Wei; Machida, Tatsuya; Chen, Chia-Lin; Kumar, Dinesh Babu Uthaya; Punj, Vasu; Winer, Peleg; Pita, Alejandro; Sher, Linda; Tahara, Stanley M.; Ray, Ratna B.; Liang, Chengyu; Chen, Lin; Tsukamoto, Hidekazu; Machida, Keigo

doi:10.1038/s41467-020-16616-8

Cited by 26 publications

(30 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, the NOTCH1 downstream effectors, HES1 and HEY1, promote integration of EMT and CSC self-renewal (31,32). Other work has shown that NOTCH1 interacts with NANOG in expanding CSCs (44). Along these lines, we found that the MUC1-CE2F1BAF pathway is necessary for expression of NOTCH1 and NANOG in PC cells.…”

Section: Muc1-c Regulates Lineage Plasticity In the Progression To Nepc By Activating In Part Asupporting

confidence: 78%

MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells

et al. 2021

View full text Add to dashboard Cite

The BAF (mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC); however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-CE2F1 pathway induces expression of embryonic stem cell esBAF components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared to CRPC, supporting involvement of MUC1-C in activating the E2F1esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-CE2F1BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness.

show abstract

Section: Muc1-c Regulates Lineage Plasticity In the Progression To Nepc By Activating In Part Asupporting

confidence: 78%

MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…PEST [17]) may be sufficient to drive tumorigenesis in some instances, the majority of solid tumors with oncogenic Notch signaling might instead harbor aberrations in regulatory proteins (e.g. NUMB [18], TBC1D15 [19]), signaling partners, or relative dosage [20]. Thus, the role of Notch in tumorigenesis may be context dependent, acting most convincingly in cells already poised for transformation.…”

Section: Gamma Secretase Inhibitors and The Notch Pathwaymentioning

confidence: 99%

“…NICD1 signaling was not sufficient to induce cancer initiation but could cooperate with AKT, Myc, and Ras/Raf/MAPK to drive formation of prostate adenocarcinoma in mice and promote more aggressive phenotypes in human prostate cancer cells [16]. Accordingly, although mutations in Notch regulatory sequences or domains (e.g., PEST [17]) may be sufficient to drive tumorigenesis in some instances, the majority of solid tumors with oncogenic Notch signaling might instead harbor aberrations in regulatory proteins (e.g., NUMB [18], TBC1D15 [19]), signaling partners, or relative dosage [20]. Thus, the role of Notch in tumorigenesis may be context dependent, acting most convincingly in cells already poised for transformation.…”

Section: Gamma Secretase Inhibitors and The Notch Pathwaymentioning

confidence: 99%

Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance

et al. 2021

View full text Add to dashboard Cite

Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem‐like cell differentiation and apoptosis, while also impairing epithelial‐to‐mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor‐intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch‐dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. Implications for Practice The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

show abstract

“…The understanding on the tumorigenesis process has been explained during decades according to the clonal evolution model. This model postulates that all cells within a tumor contribute to the maintenance of the tumor at different levels ( 1 ). In the cell, a number of genetic and epigenetic changes accumulate during time, and, by selection, the most aggressive cancer cells drive tumor progression ( 1 , 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…This model postulates that all cells within a tumor contribute to the maintenance of the tumor at different levels ( 1 ). In the cell, a number of genetic and epigenetic changes accumulate during time, and, by selection, the most aggressive cancer cells drive tumor progression ( 1 , 2 ). Therefore, any cancer cell can become highly malignant, contributing to metastases and the resistance against therapies ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

et al. 2020

View full text Add to dashboard Cite

The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo-and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-κB pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.

show abstract

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

Cited by 26 publications

References 35 publications

MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells

MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells

Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness

Contact Info

Product

Resources

About