Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

Gong, Lili; Govan, Jeane M.; Evans, Elizabeth; Dai, Hui; Wang, Edward; Lee, Szu Wei; Lin, Hui Kuan; Lazar, Alexander J.; Mills, Gordon B.; Lin, Shiaw Yih

doi:10.1080/15384101.2015.1044174

Cited by 43 publications

(47 citation statements)

References 32 publications

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“…It is increasingly evident that PTEN controls global chromatin architecture. For example, the heterochromatin structure is markedly impaired following PTEN deletion (Chen et al, 2014; Gong et al, 2015). Mechanistic studies revealed that PTEN physically interacts with a major heterochromatin protein, HP1α, and the linker histone H1.…”

Section: Pten As a Tumor Suppressormentioning

confidence: 99%

PTEN at the interface of immune tolerance and tumor suppression

et al. 2017

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BACKGROUND PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

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Section: Pten As a Tumor Suppressormentioning

confidence: 99%

PTEN at the interface of immune tolerance and tumor suppression

et al. 2017

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“…[1][2][3][4] PTEN targets phosphatidylinositol-3,4,5-triphosphate (PIP3) and antagonizes the major survival pathway regulated by phosphatidylinositol 3-kinase (PI3K)/Akt. [5][6][7] Increasing evidence indicates that nuclear PTEN has fundamental functions in maintenance of chromosomal stability, 2,[8][9][10][11][12][13][14] suggesting there are as yet unidentified mechanisms in the process of chromosome inheritance for which the function of PTEN is indispensable. It has been shown that PTEN plays an essential role in maintaining the structural integrity of individual chromosomes, 2 which supports recognition of PTEN as a guardian of the genome.…”

Section: Introductionmentioning

confidence: 99%

PTEN regulates PLK1 and controls chromosomal stability during cell division

Zhang

Hou

et al. 2016

Cell Cycle

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PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

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“…Recently, we and others have found that PTEN, which sustains chromosome condensation and heterochromatin structure [152,153], mediates fork progression and recovery during replication via recruitment of replication factor 1, Rad51 recombinase, and MCM2 helicase [167–169]. These studies highlight the essential role of PTEN in maintaining chromatin condensation and ensuring efficient recruitment of vital replication factors for genome duplication.…”

Section: Chromatin Deregulation Genomic Instability and Cancermentioning

confidence: 85%

“…Recent research has uncovered new chromatin players and novel mechanisms of chromatin regulation, which helps understand the genome-epigenome interplay. For example, the tumor suppressor PTEN has been found to promote chromatin condensation by interacting with histones and other chromatin architecture proteins [152,153]. PTEN is among the most frequently mutated genes in human cancer.…”

Section: Chromatin Deregulation Genomic Instability and Cancermentioning

confidence: 99%

“…The mechanism for these earlier observations has been uncovered only recently, which points to the direct involvement of PTEN in chromatin dynamics. PTEN interacts with histone H1 to maintain chromatin condensation and heterochromatin structure [152,153]. Loss of PTEN hinders H1-mediated loading of HP1α.…”

Section: Chromatin Deregulation Genomic Instability and Cancermentioning

confidence: 99%

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Genome maintenance in the context of 4D chromatin condensation

Yang

Shen

2016

Cell. Mol. Life Sci.

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The eukaryotic genome is packaged in the three-dimensional nuclear space by forming loops, domains and compartments in a hierarchical manner. However, when duplicated genomes prepare for segregation, mitotic cells eliminate topologically associating domains and abandon the compartmentalized structure. Alongside chromatin architecture reorganization during the transition from interphase to mitosis, cells halt most DNA-templated processes such as transcription and repair. The intrinsically condensed chromatin serves as a sophisticated signaling module subjected to selective relaxation for programmed genomic activities. To understand the elaborate genome-epigenome interplay during cell cycle progression, the steady three-dimensional genome requires a time scale to form a dynamic four-dimensional and a more comprehensive portrait. In this review, we will dissect the functions of critical chromatin architectural components in constructing and maintaining an orderly packaged chromatin environment. We will also highlight the importance of the spatially-and-temporally-conscious orchestration of chromatin remodeling to ensure high-fidelity genetic transmission.

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Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

Cited by 43 publications

References 32 publications

PTEN at the interface of immune tolerance and tumor suppression

PTEN at the interface of immune tolerance and tumor suppression

PTEN regulates PLK1 and controls chromosomal stability during cell division

Genome maintenance in the context of 4D chromatin condensation

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