Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

Mooney, Steven M.; Jolly, Mohit Kumar; Levine, Herbert; Kulkarni, Prakash

doi:10.4103/1008-682x.183570

Cited by 67 publications

(62 citation statements)

References 75 publications

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“…EMT is a carefully choreographed process that is instrumental in embryonic development, wound healing and the emergence of cancer metastasis [Mooney et al, ]. The idea that EMT is an “all or nothing” binary process is being challenged by observations that cells can undergo a partial EMT into a hybrid (E/M) phenotype.…”

Section: Discussionmentioning

confidence: 99%

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The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

et al. 2017

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More than 90% of cancer-related deaths are caused by metastasis. Epithelial-to-Mesenchymal Transition (EMT) causes tumor cell dissemination while the reverse process, Mesenchymal-to-Epithelial Transition (MET) allows cancer cells to grow and establish a potentially deadly metastatic lesion. Recent evidence indicates that in addition to E and M, cells can adopt a stable hybrid Epithelial/Mesenchymal (E/M) state where they can move collectively leading to clusters of Circulating Tumor Cells-the "bad actors" of metastasis. EMT is postulated to occur in all four major histological breast cancer subtypes. Here, we identify a set of genes strongly correlated with CDH1 in 877 cancer cell lines, and differentially expressed genes in cell lines overexpressing ZEB1, SNAIL, and TWIST. GRHL2 and ESRP1 appear in both these sets and also correlate with CDH1 at the protein level in 40 breast cancer specimens. Next, we find that GRHL2 and CD24 expression coincide with an epithelial character in human mammary epithelial cells. Further, we show that high GRHL2 expression is highly correlated with worse relapse-free survival in all four subtypes of breast cancer. Finally, we integrate CD24, GRHL2, and ESRP1 into a mathematical model of EMT regulation to validate the role of these players in EMT. Our data analysis and modeling results highlight the relationships among multiple crucial EMT/MET drivers including ZEB1, GRHL2, CD24, and ESRP1, particularly in basal-like breast cancers, which are most similar to triple-negative breast cancer (TNBC) and are considered the most dangerous subtype. J. Cell. Biochem. 118: 2559-2570, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

“…90% of cancer deaths are a direct result of metastasis [Jia et al, ]. Once the tumor cells reach an advanced stage and are able to undergo an Epithelial‐to‐Mesenchymal Transition (EMT), they become motile and can leave their tissue of origin [Mooney et al, ]. EMT is also implicated in chemoresistance [Fischer et al, ; Zheng et al, ].…”

Section: Introductionmentioning

confidence: 99%

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

et al. 2017

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“…However, during tumor progression, many of the molecular brakes against phenotypic plasticity are deregulated, enabling cancer cells to behave as 'moving targets' that can play 'hide-and-seek' with multiple therapeutic regimes (Roesch, 2015;Varga et al, 2014). In addition, these phenotypic conversions can facilitate adaptation by enabling genetically identical cells to exhibit a diverse set of phenotypes and may also help fuel genetic evolution of cancer cells (Brooks et al, 2015;Mooney et al, 2016;Yadav et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

et al. 2017

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Phenotypic plasticity, the ability of cells to reversibly alter their phenotypes in response to signals, presents a significant clinical challenge to treating solid tumors. Tumor cells utilize phenotypic plasticity to evade therapies, metastasize, and colonize distant organs. As a result, phenotypic plasticity can accelerate tumor progression. A well‐studied example of phenotypic plasticity is the bidirectional conversions among epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M) phenotype(s). These conversions can alter a repertoire of cellular traits associated with multiple hallmarks of cancer, such as metabolism, immune evasion, invasion, and metastasis. To tackle the complexity and heterogeneity of these transitions, mathematical models have been developed that seek to capture the experimentally verified molecular mechanisms and act as ‘hypothesis‐generating machines’. Here, we discuss how these quantitative mathematical models have helped us explain existing experimental data, guided further experiments, and provided an improved conceptual framework for understanding how multiple intracellular and extracellular signals can drive E/M plasticity at both the single‐cell and population levels. We also discuss the implications of this plasticity in driving multiple aggressive facets of tumor progression.

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“…IDPs also participate in higher order phenomena, such as regulation of the cell division cycle (10)(11)(12), circadian rhythmicity (13,14), and phenotypic plasticity (15,16). Recent evidence suggests that several IDPs can act in a prion-like manner to create protein-based molecular memories that drive the emergence and inheritance of biological traits (17), further emphasizing their importance in state (or phenotype) switching.…”

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confidence: 99%

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

Kulkarni

Jolly

Jia

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) that lack a unique 3D structure and comprise a large fraction of the human proteome play important roles in numerous cellular functions. ProstateAssociated Gene 4 (PAGE4) is an IDP that acts as a potentiator of the Activator Protein-1 (AP-1) transcription factor. HomeodomainInteracting Protein Kinase 1 (HIPK1) phosphorylates PAGE4 at S9 and T51, but only T51 is critical for its activity. Here, we identify a second kinase, CDC-Like Kinase 2 (CLK2), which acts on PAGE4 and hyperphosphorylates it at multiple S/T residues, including S9 and T51. We demonstrate that HIPK1 is expressed in both androgendependent and androgen-independent prostate cancer (PCa) cells, whereas CLK2 and PAGE4 are expressed only in androgendependent cells. Cell-based studies indicate that PAGE4 interaction with the two kinases leads to opposing functions. HIPK1-phosphorylated PAGE4 (HIPK1-PAGE4) potentiates c-Jun, whereas CLK2-phosphorylated PAGE4 (CLK2-PAGE4) attenuates c-Jun activity. Consistent with the cellular data, biophysical measurements (small-angle X-ray scattering, single-molecule fluorescence resonance energy transfer, and NMR) indicate that HIPK1-PAGE4 exhibits a relatively compact conformational ensemble that binds AP-1, whereas CLK2-PAGE4 is more expanded and resembles a random coil with diminished affinity for AP-1. Taken together, the results suggest that the phosphorylation-induced conformational dynamics of PAGE4 may play a role in modulating changes between PCa cell phenotypes. A mathematical model based on our experimental data demonstrates how differential phosphorylation of PAGE4 can lead to transitions between androgen-dependent and androgen-independent phenotypes by altering the AP-1/androgen receptor regulatory circuit in PCa cells.intrinsic disorder | androgen resistance | prostate cancer | PAGE-4 | phenotypic heterogeneity C ontrary to conventional wisdom that structure defines protein function (1), it is now increasingly evident that a large fraction of the human proteome is composed of intrinsically disordered proteins (IDPs) lacking rigid 3D structure (2-4). IDPs exist as conformational ensembles that are highly malleable, facilitating their interactions with multiple partners. These interactions are "wired" to form scale-free networks (5, 6) that represent the main conduit of information flow in the cell. Furthermore, the organization and properties of such protein interaction networks are evolutionarily conserved, underscoring their functional significance (7).By occupying hub positions in such networks, IDPs play critical roles in many biological processes, such as transcription, translation, and signaling (8, 9). IDPs also participate in higher order phenomena, such as regulation of the cell division cycle (10-12), circadian rhythmicity (13, 14), and phenotypic plasticity (15, 16). Recent evidence suggests that several IDPs can act in a prion-like manner to create protein-based molecular memories that drive the emergence and inheritance of biological traits (17), furt...

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Phenotypic plasticity in prostate cancer: role of intrinsically disordered proteins

Cited by 67 publications

References 75 publications

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer

Epithelial/mesenchymal plasticity: how have quantitative mathematical models helped improve our understanding?

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

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