Augmentation of Myc-Dependent Mitotic Gene Expression by the Pygopus2 Chromatin Effector

Andrews, Phillip; Popadiuk, Catherine; Belbin, Thomas J.; Kao, Kenneth R.

doi:10.1016/j.celrep.2018.04.020

Cited by 12 publications

(22 citation statements)

References 69 publications

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“…Consistent with a role of Pygo2 in proliferation (20), our results demonstrate that loss of Pygo2-histone binding results in smaller tumors due to a proliferation defect rather than an increase in apoptosis. Interestingly, the phenotype was not accentuated by an additional loss of Pygo1 confirming previous observations that Pygo1 is functionally not as relevant as Pygo2 (9)(10)(11)(12).…”

Section: Discussionsupporting

confidence: 88%

“…At actively transcribing gene loci, Pygo2 binds activating histone marks, such as bi-or trimethylated histones (H3K4me 2/3 ), and recruits histone acetyltransferases (HAT), which in turn promote an open chromatin structure (17)(18)(19). Moreover, by acting as an epigenetic accessory protein, Pygo2 drives Myc-dependent activation of mitosis-related genes (20). Befitting its role in proliferation, an increased expression of Pygo2 has been observed in several malignancies, including ovarian cancer (21), glioma (22), lung cancer (23), hepatocellular carcinoma (24), and prostate cancer (25).…”

Section: Introductionmentioning

confidence: 99%

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A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer

et al. 2020

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◥Pygopus 2 (Pygo2) is a coactivator of Wnt/b-catenin signaling that can bind bi-or trimethylated lysine 4 of histone-3 (H3K4me 2/3 ) and participate in chromatin reading and writing. It remains unknown whether the Pygo2-H3K4me 2/3 association has a functional relevance in breast cancer progression in vivo. To investigate the functional relevance of histone-binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model where binding of Pygo2 to H3K4me 2/3 was rendered ineffective. Loss of Pygo2-histone interaction resulted in smaller, differentiated, and less metastatic tumors, due, in part, to decreased canonical Wnt/b-catenin signaling. RNA-and ATAC-sequencing analyses of tumor-derived cell lines revealed downregulation of TGFb signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate that could be reversed by inhibition of PDGFR activity. Mechanistically, the Pygo2-histone interaction potentiated Wnt/b-catenin signaling, in part, by repressing the expression of Wnt signaling antagonists. Furthermore, Pygo2 and b-catenin regulated the expression of miR-29 family members, which, in turn, repressed PDGFR expression to promote dedifferentiation of wild-type Pygo2 mammary epithelial tumor cells. Collectively, these results demonstrate that the histone binding function of Pygo2 is important for driving dedifferentiation and malignancy of breast tumors, and loss of this binding activates various differentiation pathways that attenuate primary tumor growth and metastasis formation. Interfering with the Pygo2-H3K4me 2/3 interaction may therefore serve as an attractive therapeutic target for metastatic breast cancer.Significance: Pygo2 represents a potential therapeutic target in metastatic breast cancer, as its histone-binding capability promotes b-catenin-mediated Wnt signaling and transcriptional control in breast cancer cell dedifferentiation, EMT, and metastasis.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer

et al. 2020

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“…This result is consistent with our recent report demonstrating that the loss of Pygous 2 interaction with histones in tumors of MMTV-PyMT transgenic mice resulted in smaller and more differentiated tumors with less metastasis [35]. However, we did not see a significant reduction of tumor cell proliferation or increase in apoptosis, as expected from the reported role of Pygopus 2 in cell proliferation [36].…”

Section: Discussionsupporting

confidence: 93%

The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

et al. 2021

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Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.

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“…RASFF1 prevents cell proliferation by negative regulating of G1/S-phase transition of the cell cycle by reducing the accumulation of cyclin D1 protein. Moreover, promoter hypermethylation of stratifin, which inhibits the cyclin B1-CD2 complex from entering the nucleus by enforcing a G2/M arrest was associated with CaP progression (Singh & Sharma 2017), and loss of Pygopus (Pygo) 2 chromatin effector enhances Myc oncogenic activity in CaP (Andrews et al 2018).…”

Section: Epigenetic Changesmentioning

confidence: 99%

Novel insights in cell cycle dysregulation during prostate cancer progression

Ben-Salem

Venkadakrishnan

Heemers

2021

Endocrine-Related Cancer

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Prostate cancer (CaP) remains the second leading cause of cancer deaths in western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators, and address challenges and limitations approaches modulating their action, for CaP treatment.

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Augmentation of Myc-Dependent Mitotic Gene Expression by the Pygopus2 Chromatin Effector

Cited by 12 publications

References 69 publications

A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer

A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer

The interactions of Bcl9/Bcl9L with β-catenin and Pygopus promote breast cancer growth, invasion, and metastasis

Novel insights in cell cycle dysregulation during prostate cancer progression

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