Roles of OCT4 in tumorigenesis, cancer therapy resistance and prognosis

Villodre, Emilly Schlee; Kipper, Franciele; Pereira, Mariana Brutschin; Lenz, Guido

doi:10.1016/j.ctrv.2016.10.003

Cited by 114 publications

(80 citation statements)

References 101 publications

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“…As Oct4 (72)(73)(74) and Cav-1 (75)(76)(77)(78) were found in various types of normal and cancerous cells, and the function of Oct4 in the regulation of stem cell properties was widely demonstrated in both CSC and noncancerous stem cells (72)(73)(74), it is interesting to investigate for the Cav-1:Oct4 suppressor complex in normal stem cells. Also, the abundance of Oct4 in cancer cells may be enhanced by the fact that the cancer cells frequently reside in a high NO concentration environment (19) or gain of Akt function (79).…”

Section: Nitric Oxide Maintains Oct4 By Dissociating Caveolin-1mentioning

confidence: 99%

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Maiuthed

Bhummaphan

Luanpitpong

et al. 2018

Journal of Biological Chemistry

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Cancer stem cells (CSCs) are unique populations of cells that can self-renew and generate different cancer cell lineages. Although CSCs are believed to be a promising target for novel therapies, the specific mechanisms by which these putative therapeutics could intervene are less clear. Nitric oxide (NO) is a biological mediator frequently up-regulated in tumors and has been linked to cancer aggressiveness. Here, we search for targets of NO that could explain its activity. We find that it directly affects the stability and function of octamer-binding transcription factor 4 (Oct4), known to drive the stemness of lung cancer cells. We demonstrated that NO promotes the CSC-regulatory activity of Oct4 through a mechanism that involves complex formation between Oct4 and the scaffolding protein caveolin-1 (Cav-1). In the absence of NO, Oct4 forms a molecular complex with Cav-1, which promotes the ubiquitin-mediated proteasomal degradation of Oct4. NO promotes Akt-dependent phosphorylation of Cav-1 at tyrosine 14, disrupting the Cav-1:Oct4 complex. Site-directed mutagenesis and computational modeling studies revealed that the hydroxyl moiety at tyrosine 14 of Cav-1 is crucial for its interaction with Oct4. Both removal of the hydroxyl via mutation to phenylalanine and phosphorylation lead to an increase in binding free energy (Δ) between Oct4 and Cav-1, destabilizing the complex. Together, these results unveiled a novel mechanism of CSC regulation through NO-mediated stabilization of Oct4, a key stem cell transcription factor, and point to new opportunities to design CSC-related therapeutics.

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Section: Nitric Oxide Maintains Oct4 By Dissociating Caveolin-1mentioning

confidence: 99%

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Maiuthed

Bhummaphan

Luanpitpong

et al. 2018

Journal of Biological Chemistry

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“…9). These shared targets are highly enriched for cancer, cell signaling and stem cell related gene ontology categories, fitting with data linking Oct4 to numerous cancer types, and to the regulation of stem cell-like properties of tumors (Murakami et al, 2015; Kaufhold et al, 2016; Villodre et al, 2016). These findings are also relevant in the converse context of the tumorigenic properties of pluripotent stem cells, which form teratomas when injected into mice, and suggest that Dppa4 gene targets regulate a number of the shared properties at the intersection of stem cells and cancer.…”

Section: Discussionmentioning

confidence: 92%

Genomic functions of developmental pluripotency associated factor 4 (Dppa4) in pluripotent stem cells and cancer

et al. 2018

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Developmental pluripotency associated factor 4 (Dppa4) is a highly specific marker of pluripotent cells, and is also overexpressed in certain cancers, but its function in either of these contexts is poorly understood. In this study, we use ChIP-Seq to identify Dppa4 binding genome-wide in three distinct cell types: mouse embryonic stem cells (mESC), embryonal carcinoma cells, and 3T3 fibroblasts ectopically expressing Dppa4. We find a core set of Dppa4 binding sites shared across cell types, and also a substantial number of sites unique to each cell type. Across cell types Dppa4 shows a preference for binding to regions with active chromatin signatures, and can influence chromatin modifications at target genes. In 3T3 fibroblasts with enforced Dppa4 expression, Dppa4 represses the cell cycle inhibitor Cdkn2c and activates Ets family transcription factor Etv4, leading to alterations in the cell cycle that likely contribute to the oncogenic phenotype. Dppa4 also directly regulates Etv4 in mESC but represses it in this context, and binds with Oct4 to a set of shared targets that are largely independent of Sox2 and Nanog, indicating that Dppa4 functions independently of the core pluripotency network in stem cells. Together these data provide novel insights into Dppa4 function in both pluripotent and oncogenic contexts.

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“…OCT4 is crucial for stem cell pluripotency and plays an important role in embryonic development. Several reports note that OCT4 also contributes to tumorigenesis and impacts cancer in a context‐dependent manner . Here, we have tested eight OCT4 mutants and identified two (OCT4FL‐K128N and OCT4FL C198R) that enhance cellular reprogramming.…”

Section: Discussion and Outlookmentioning

confidence: 94%

Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

et al. 2019

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The functional consequences of cancer‐associated missense mutations are unclear for the majority of proteins. We have previously demonstrated that the activity of SOX and Pit‐Oct‐Unc (POU) family factors during pluripotency reprogramming can be switched and enhanced with rationally placed point mutations. Here, we interrogated cancer mutation databases and identified recurrently mutated positions at critical structural interfaces of the DNA‐binding domains of paralogous SOX and POU family transcription factors. Using the conversion of mouse embryonic fibroblasts to induced pluripotent stem cells as functional readout, we identified several gain‐of‐function mutations that enhance pluripotency reprogramming by SOX2 and OCT4. Wild‐type SOX17 cannot support reprogramming but the recurrent missense mutation SOX17‐V118M is capable of inducing pluripotency. Furthermore, SOX17‐V118M promotes oncogenic transformation, enhances thermostability and elevates cellular protein levels of SOX17. We conclude that the mutational profile of SOX and POU family factors in cancer can guide the design of high‐performance reprogramming factors. Furthermore, we propose cellular reprogramming as a suitable assay to study the functional impact of cancer‐associated mutations.

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Roles of OCT4 in tumorigenesis, cancer therapy resistance and prognosis

Cited by 114 publications

References 101 publications

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Genomic functions of developmental pluripotency associated factor 4 (Dppa4) in pluripotent stem cells and cancer

Cancer‐associated missense mutations enhance the pluripotency reprogramming activity of OCT4 and SOX17

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