CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle

Slotta, Carsten; Schlüter, Thomas; Ruiz-Perera, Lucia Mercedes; Kadhim, Hussamadin M.; Tertel, Tobias; Henkel, Elena; Hübner, Wolfgang; Greiner, Johannes F. W.; Huser, Thomas; Kaltschmidt, Barbara; Kaltschmidt, Christian

doi:10.1371/journal.pone.0182373

Cited by 18 publications

(16 citation statements)

References 59 publications

(76 reference statements)

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“…Furthermore, in hepatocytes c‐Rel promoter interaction with the mitotic regulator FOXM1 was shown . In human keratinocytes, c‐Rel suppression leads to an increase in G2/M phase cells and aberrant mitotic spindle appearance, and recently, also CRISPR/Cas9‐mediated c‐Rel knockout induced a delay in early mitotic phase in HeLa cells suggesting diverse functions for c‐Rel in cell cycle regulation of certain cell types.…”

Section: Discussionmentioning

confidence: 96%

c‐Rel is a cell cycle modulator in human melanoma cells

Priebe

Dewert

Amschler

et al. 2018

Experimental Dermatology

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Melanoma progression and resistance to therapy are associated with faulty regulation of signalling molecules including the central transcription factor NF‐κB. Increased expression of the c‐Rel subunit of NF‐κB has been described in progressing melanoma, though mechanistic implications of this upregulation remain unclear. To elucidate the functional role of c‐Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c‐Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c‐Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, chromosomal stability. Our results highlight a novel tumor‐promoting function of c‐Rel in human melanoma cells through governing cell cycle regulation.

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Section: Discussionmentioning

confidence: 96%

c‐Rel is a cell cycle modulator in human melanoma cells

Priebe

Dewert

Amschler

et al. 2018

Experimental Dermatology

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“…To provide an overview on the occurrences of distinct NF-κB subunits in cancer subtypes, we assessed the overexpression of the NF-κB subunits RELA, RELB, and c-REL in human cancers by database mining, using COSMIC ( Table 1 ) [ 12 , 37 ].…”

Section: Differential Roles Of Nf-κb Subunits In Cancermentioning

confidence: 99%

Subunit-Specific Role of NF-κB in Cancer

et al. 2018

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The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-κB subunits RELA, RELB, and c-REL (referring to the v-REL, which is the oncogene of Reticuloendotheliosis virus strain T) as well as of their upstream kinase inhibitor, namely inhibitor of κB kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-κB, and suggest a much more elaborated mode of NF-κB regulation, indicating a tumor type-specific upregulation of the NF-κB subunits. We further discuss recent findings showing the diverse roles of NF-κB signaling in cancer development and metastasis in a subunit-specific manner, emphasizing their specific transcriptional activity and the role of autoregulation. While non-canonical NF-κB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-κB RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-κB c-REL in regulating cancer-targeting immune responses. In addition, current strategies and ongoing clinical trials are summarized, which utilize genome editing or drugs to inhibit the NF-κB subunits for cancer treatment.

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“…In another human epithelial cell type, HeLa cells, knockdown of c‐Rel using CRISPR/Cas9, had dramatic effects on proliferation but did not impact apoptosis. An interesting observation from this study was that c‐Rel knockdown resulted in increased resistance to chemotherapeutics including cisplatin and 5 Fluoro 2 deoxyuridine …”

Section: The Nf‐κb Family Of Transcription Factorsmentioning

confidence: 86%

“…An interesting observation from this study was that c-Rel knockdown resulted in increased resistance to chemotherapeutics including cisplatin and 5 Fluoro 2 deoxyuridine. 69…”

Section: A Specific Role For Nf-κb/c-rel In Epidermal Homeostasismentioning

confidence: 99%

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

King

George

Sakakibara

et al. 2019

Molecular Carcinogenesis

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Overexpression of ΔNp63α, a member of the p53/p63/p73 family of transcription factors, is a molecular attribute of human squamous cancers of the head and neck, lung and skin. The TP63 gene plays important roles in epidermal morphogenesis and homeostasis, regulating diverse biological processes including epidermal fate decisions and keratinocyte proliferation and survival. When overexpressed experimentally in primary mouse keratinocytes, ΔNp63α maintains a basal cell phenotype including the loss of normal calcium‐mediated growth arrest, at least in part through the activation and enhanced nuclear accumulation of the c‐rel subunit of NF‐κB (Nuclear Factor‐kappa B). Initially identified for its role in the immune system and hematopoietic cancers, c‐Rel has increasingly been associated with solid tumors and other pathologies. ΔNp63α and c‐Rel have been shown to be associated in the nuclei of ΔNp63α overexpressing human squamous carcinoma cells. Together, these transcription factors cooperate in the transcription of genes regulating intrinsic keratinocyte functions, as well as the elaboration of factors that influence the tumor microenvironment (TME). This review provides an overview of the roles of ΔNp63α and c‐Rel in normal epidermal homeostasis and elaborates on how these pathways may intersect in pathological conditions such as cancer and the associated TME.

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CRISPR/Cas9-mediated knockout of c-REL in HeLa cells results in profound defects of the cell cycle

Cited by 18 publications

References 59 publications

c‐Rel is a cell cycle modulator in human melanoma cells

c‐Rel is a cell cycle modulator in human melanoma cells

Subunit-Specific Role of NF-κB in Cancer

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

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