OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness

Comisso, Elisa; Scarola, Michele; Rosso, Massimo; Piazza, Silvano; Marzinotto, Stefania; Ciani, Yari; ­Orsaria, Maria; Mariuzzi, Laura; Schneider, Claudio; Schoeftner, Stefan; Benetti, Roberta

doi:10.1038/onc.2017.20

Cited by 40 publications

(36 citation statements)

References 48 publications

(74 reference statements)

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“…Our work demonstrates that Oct4 expression impacts diversely on HPV(+) and HPV(-) cervical tumors. Oct4 has previously been reported to accelerate proliferation in cancer cells [10,[33][34]. In cervical cancer cells tested here, we observed a similar effect of Oct4 on proliferation but only in the HPV(-) cell line C33A.…”

Section: Plos Pathogenssupporting

confidence: 81%

“…The expression of Oct4 was previously reported in some tumors [6,[8][9][10]12], but its role in somatic and cancer cells is still controversial [1][2][3][4][5]. To investigate Oct4 expression in cervical cancer, we extracted Oct4 gene expression data from the Cancer Genome Atlas (TCGA) CESC dataset and compared them to the normalised corresponding levels using normal cervical tissue that was extracted from the GTEx, FANTOM5 and HPA projects ( Fig 1A).…”

Section: Oct4 Is Expressed In Cervical Cancersmentioning

confidence: 99%

“…Initial evidence suggests that Oct4 acts as a rheostat gene controlling the development and progression of malignancy in germ cells [6]. More recent evidence reports the expression of Oct4 in somatic malignancies, such as prostate [8], breast [9], ovarian [10], hepatocellular [11], head and neck [12] and cervical [13] cancers. As a cancer marker, Oct4 was recently associated with poor prognosis in hepatocellular carcinomas [14].…”

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers

et al. 2020

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Octamer binding transcription factor-4 (Oct4), is highly expressed in stem cells and has indispensable roles in pluripotency and cellular reprogramming. In contrast to other factors used for cellular reprogramming, a role for Oct4 outside embryonic stem cells has been elusive and highly controversial. Emerging evidence implicates Oct4 in the carcinogenic process, but the mechanism through which Oct4 may be functioning in cancers is not fully appreciated. Here, we provide evidence that Oct4 is expressed in human cervical cancer and this expression correlates with the presence of the human papillomavirus (HPV) oncogenes E6 and E7. Surprisingly, the viral oncogenes can complement exogenously provided Oct4 in reprogramming assays, providing functional validation for their ability to activate Oct4 transcription in Mouse Embryonic Fibroblasts (MEFs). To interrogate potential roles of Oct4 in cervical cancers we knocked-down Oct4 in HPV(+) (HeLa & CaSki) and HPV(-) (C33A) cervical cancer cell lines and found that Oct4 knockdown attenuated clonogenesis, only in the HPV(+) cells. More unexpectedly, cell proliferation and migration, were differentially affected in HPV(+) and HPV(-) cell lines. We provide evidence that Oct4 interacts with HPV E7 specifically at the CR3 region of the E7 protein and that introduction of the HPV oncogenes in C33A cells and human immortalised keratinocytes generates Oct4-associated transcriptional and phenotypic patterns, which mimic those seen in HPV(+) cells. We propose that a physical interaction of Oct4 with E7 regulates its activity in HPV(+) cervical cancers in a manner not seen in other cancer types.

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Section: Plos Pathogenssupporting

confidence: 81%

Section: Oct4 Is Expressed In Cervical Cancersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers

et al. 2020

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“…Inhibition of the OCT4 expression reduces the CCND expression, and cause leaving the cells in the G1 phase (28). Inhibiting the expression of the OCT4 gene prolongs the cell division time and also reduces the proliferation of cancer cells (29). The inhibition of the expression of the OCT4 gene causes the cell cycle to stop, thereby reducing the proliferative capacity and creating a colony in the acute myeloid cell line (30).…”

Section: Discussionmentioning

confidence: 99%

OCT4 expression regulated apoptosis and cell cycle in myeloma cells

Niknamian

2018

Preprint

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“…Oct1 functions physiologically not to promote tumors, but rather to promote stem cell potency. The stem cell properties that Oct1 promotes are largely pro-oncogenic, but in one respect Oct1 can be tumor suppressive: like its paralog Oct4 [40], Oct1 promotes mitotic stability [16], a hallmark of stem cells [40][41][42]. To test the hypothesis that loss of Oct1 can accelerate tumor initiation in models of malignancy dependent on mitotic errors and LOH, we used conditional deletion of the Apc gene, which is mutated in a large proportion of human colon cancers [43].…”

Section: Oct1 Restricts Tumorigenicity In a Model Of Colon Cancer Drimentioning

confidence: 99%

Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

Vázquez-Arreguín

Bensard

et al. 2018

Preprint

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The transcription factor Oct1/Pou2f1 promotes poised gene expression states, mitotic stability, glycolytic metabolism and other characteristics of stem cell potency. To determine the effect of Oct1 loss on stem cell maintenance and malignancy, we deleted Oct1 in two different mouse gut stem cell compartments. Oct1 deletion preserved homeostasis in vivo and the ability to generate cultured organoids in vitro, but blocked the ability to regenerate after treatment with dextran sodium sulfate, and the ability to maintain organoids after passage. In a chemical model of colon cancer, loss of Oct1 in the colon severely restricted tumorigenicity. In contrast, loss of one or both Oct1 alleles progressively increased tumor burden in a colon cancer model driven by loss of heterozygosity of the tumor suppressor gene Apc. The different outcomes are consistent with prior findings that Oct1 promotes mitotic stability, and consistent with different gene expression signatures associated with the two models. These results reveal that Oct1 is selectively required for gut regeneration, and has potent effects in colon malignancy, with outcome (pro-oncogenic or tumor suppressive) dictated by tumor etiology. Author summaryColorectal cancer is the second leading cause of cancer death in the United States. Approximately 35% of diagnosed patients eventually succumb to disease. The high incidence and mortality due to colon cancer demand a better understanding of factors controlling the physiology and pathophysiology of the gastrointestinal tract. Previously, we and others showed that the widely expressed transcription factor is expressed at higher protein levels in stem cells, including intestinal stem cells. In this study we use a conditional mouse Oct1 (Pou2f1) allele deleted in two different intestinal stem cell compartments. The results indicate that Oct1 loss is dispensable for maintenance of the mouse gut, but required for regeneration. We also tested Oct1 loss in the context of two different mouse colon cancer models. We find that Oct1 loss has opposing effects in the two models, and further that the two models are associated with different gene expression signatures. The differentially expressed genes are enriched for previously identified Oct1 targets, suggesting that differential gene control by Oct1 is one mechanism underlying different outcomes.

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OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness

Cited by 40 publications

References 48 publications

Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers

Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers

OCT4 expression regulated apoptosis and cell cycle in myeloma cells

Oct1/Pou2f1 is selectively required for gut regeneration and regulates gut malignancy

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