YY1 PcG function as a Potential cancer Therapeutic Target

Basu, Arindam; Hodawadekar, Suchita; Andrews, Omozusi E.; Knox, Antionette; Pan, Xuan; Wilkinson, Frank H.; Atchison, Michael L.

doi:10.1615/forumimmundisther.v1.i1-2.30

Cited by 3 publications

(6 citation statements)

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“…YY1 antagonizes p53 (Sui et al, 2004;Yakovleva et al, 2004), with its role in p53-deficient breast cancer unclear. YY1 recruits Ezh2 for gene silencing (Wilkinson et al, 2006), while disrupted YY1-Ezh2 interaction did not affect global histone H3K27 methylation (Basu et al, 2010).…”

Section: Introductionmentioning

confidence: 92%

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation

Zhang

Wan

Shi

et al. 2016

Journal of Molecular Cell Biology

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Yin Yang 1 (YY1) regulates both gene expression and protein modifications, and has shown a proliferative role in cancers. In this study, we demonstrate that YY1 promotes AKT phosphorylation at S473, a marker of AKT activation. YY1 expression positively correlated with AKT(S473) phosphorylation in a tissue microarray and cultured cells of breast cancer, but negatively associated with the distant metastasis-free survival of 166 breast cancer patients. YY1 promotes AKT phosphorylation at S473 through direct interaction with AKT, and the AKT-binding site is mapped to the residues G201-S226 on YY1. These residues are also involved in YY1 interaction with Mdm2, Ezh2, and E1A, and thus are designated as the oncogene protein binding (OPB) domain. YY1-promoted AKT phosphorylation relies on the OPB domain but is independent of either transcriptional activity of YY1 or the activity of phosphoinositide-3-kinases. We also determine that YY1-promoted mTORC2 access to AKT leads to its phosphorylation at S473. Importantly, a peptide based on the OPB domain blocks YY1 interaction with AKT and reduces AKT phosphorylation and cell proliferation. Thus, we demonstrate for the first time that YY1 promotes mTORC2-mediated AKT activation and disrupting YY1-AKT interaction by OPB domain-based peptide may represent a potential strategy for cancer therapy.

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Section: Introductionmentioning

confidence: 92%

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation

Zhang

Wan

Shi

et al. 2016

Journal of Molecular Cell Biology

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“…We used 26 amino acid small peptide inhibitors (cell-penetrating peptides; cell-penetrating peptide inhibitors) that cross the cell membrane to show that the YY1 REPO domain peptide can indeed inhibit prostate cancer cell growth, as well as growth of an Abelson-transformed pro-B cell line. 112 We found that this inhibition is at least in part due to inducing cell death by stimulating apoptosis. 112 We propose that the REPO domain peptide functions to inhibit cancer cell growth by competitively inhibiting YY1 interaction with PcG proteins, thus ablating PcG-dependent repression (Fig.…”

Section: Mechanisms Of Yin Yang 1 Function In Oncogenesismentioning

confidence: 79%

“…112 We found that this inhibition is at least in part due to inducing cell death by stimulating apoptosis. 112 We propose that the REPO domain peptide functions to inhibit cancer cell growth by competitively inhibiting YY1 interaction with PcG proteins, thus ablating PcG-dependent repression (Fig. 3).…”

Section: Mechanisms Of Yin Yang 1 Function In Oncogenesismentioning

confidence: 79%

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Mechanisms of Yin Yang 1 in Oncogenesis: The Importance of Indirect Effects

et al. 2011

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Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that performs numerous functions including transcriptional regulation, cell growth control, apoptosis, large-scale chromosomal dynamics, and X-chromosome inactivation. YY1 clearly is able to control cell functions, including proliferation, by acting as a transcription factor either to activate or repress specific genes. Based on its ability to regulate cell growth control genes, it has been argued that YY1 can function as an oncogene that initiates oncogenesis. Although this is an attractive hypothesis, no reports indicate that YY1 can acutely transform cells in culture or form tumors within animals when overexpressed. Thus, it remains unclear whether YY1 is a “classic” oncogene. However, YY1 controls many diverse cell functions, and these functions may provide clues to its role in oncogenesis. We propose that in many cases YY1 may function in oncogenesis and disease progression through “indirect” effects by virtue of its role in either recruiting Polycomb group proteins to DNA, regulating mutator protein accumulation, controlling large-scale chromosomal dynamics or genomic integrity. Disruption of these functions may causally initiate cancer or may contribute to disease progression. Targeting YY1 functions provides possible avenues for clinical intervention.

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“…YY1 is well known for its ability to both activate and repress transcription and derives its name from these dual functions (Park and Atchison 1991; Seto et al 1991; Shi et al 1991). Its activation properties map to the N-terminal regions, whereas repression functions map to histone deacetylase binding regions, as well as to a small 25 amino acid segment that supports Polycomb-group repression (the REPO domain) (Bushmeyer et al 1995; Austen et al 1997; Galvin and Shi 1997; Thomas and Seto 1999; Satjin et al 2001; Atchison et al 2003; Srinivasan and Atchison 2004; Wilkinson et al 2006; Basu et al 2010). In addition, YY1 can self-associate providing a mechanism for it to bridge promoters and enhancers via long-distance DNA interactions which have been observed in B, T, neural, erythroid, and stem cell systems (Hwang et al 2013; Medvedovic et al 2013; Mehra et al 2016; Beagan et al 2017; Dong et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Unusual lineage plasticity revealed by YY1 knockout in pro-B cells

Banerjee,

Sanyal,

Hodawadekar

et al. 2024

Preprint

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During B cell development, cells progress through multiple developmental stages with the pro-B cell stage defining commitment to the B cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We find here that knockout of YY1 at the pro-B cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system, as well as in vivo after injection into sub-lethally irradiated Rag1-/- mice. These T lineage-like cells lose their B lineage transcript profile and gain a T cell lineage profile. Single cell-RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages indicating unusual linage plasticity. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 likely regulates commitment in multiple cell lineages.

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YY1 PcG function as a Potential cancer Therapeutic Target

Cited by 3 publications

References 0 publications

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation

Yin Yang 1 promotes mTORC2-mediated AKT phosphorylation

Mechanisms of Yin Yang 1 in Oncogenesis: The Importance of Indirect Effects

Unusual lineage plasticity revealed by YY1 knockout in pro-B cells

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