Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Li, Li; Guturi, Kiran Kumar Naidu; Gautreau, Brandon; Patel, Parasvi S.; Saad, Amine; Morii, Mayako; Mateo, Francesca; Palomero, Luís; Barbour, Haithem; Gómez, Antonio; Ng, Deborah; Kotlyar, Max; Pastrello, Chiara; Jackson, Hartland W.; Khokha, Rama; Jurišica, Igor; Affar, El Bachir; Raught, Brian; Sánchez, Otto; Alaoui‐Jamali, Moulay A.; Pujana, Miguel Ángel; Hakem, Anne; Hakem, Razq

doi:10.1172/jci120401

Cited by 32 publications

(21 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ubiquitin E3 ligase RNF8, which primarily functions in transducing DSB signals by conjugating ubiquitin to histones [22], has been reported to participate in tumorigenesis because RNF8 knockout mice develop various tumors spontaneously [44][45], indicating a negative role of RNF8 in tumorigenesis. However, RNF8 appears to have the opposite effect in tumor progression according to recent studies, because it promoted breast cancer proliferation and metastasis by affecting the Wnt/β-catenin pathway and activating the activity of transcription factors such as Twist and ERα [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

RNF8 induces β-catenin-mediated c-Myc expression and promotes colon cancer proliferation

et al. 2020

View full text Add to dashboard Cite

DNA damage signals transducer RING finger protein 8 (RNF8) is involved in maintaining genomic stability by facilitating the repair of DNA double-strand breaks (DSB) via ubiquitin signaling. By analyzing the TCGA database and colon cancer tissue microarrays, we found that the expression level of RNF8 was positively correlated with that of c-Myc in colon cancer, which were closely associated with poor survival of colon cancer patients. Furthermore, overexpressing and knocking down RNF8 increased and decreased the expression of c-Myc in colon cancer cells, respectively. In addition, RNF8 interacted with β-catenin and facilitated its nuclear translocation by conjugating K63 polyubiquitination on it. These observations suggested a de novo role of RNF8 in promoting the progression of colon cancer by inducing β-catenin-mediated c-Myc expression.

show abstract

Section: Discussionmentioning

confidence: 99%

RNF8 induces β-catenin-mediated c-Myc expression and promotes colon cancer proliferation

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A recent study showed that RNF8 suppressed mammary tumorigenesis [8] (figure 2). The loss of RNF8 in female mouse mammary epithelium cells (MECs) caused spontaneous mammary tumors in mice.…”

Section: Tumorigenesis and Cancer Progressionmentioning

confidence: 98%

“…Genomic instability is known as a pivotal cause of tumorigenesis [64]. Furthermore, female mice with deficiency of RNF8 in MECs exhibit spontaneous mammary tumors, since the loss of RNF8 results in impaired DSB repair and sustained activation of Notch signaling [8]. These findings indicate that RNF8 probably protects against tumorigenesis in some contexts.…”

Section: Conclusion Remarks and Perspectivesmentioning

confidence: 99%

“…RNF8 is also an essential factor for protection of telomere end integrity and regulates cell cycle progression. Deficiency of RNF8 in mice led to tumorigenesis, which might be caused by genomic instability [7,8]. However, RNF8 may have dual effects on tumorigenesis, as recent reports showed that RNF8 promoted tumor growth and metastasis through coactivating the transactivation of certain transcription factors [9,10].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer

Zhou¹,

Yi²,

Wang³

et al. 2019

Int. J. Biol. Sci.

View full text Add to dashboard Cite

The really interesting new gene (RING) finger protein 8 (RNF8) is a central factor in DNA double strand break (DSB) signal transduction. DSB damage is the most toxic type of DNA damage to cells and is related to genomic instability. Multiple roles for RNF8 have been identified in DNA damage response as well as in other functions, such as telomere protection, cell cycle control and transcriptional regulation. These functions are closely correlated to tumorigenesis and cancer progression. Indeed, deficiency of RNF8 caused spontaneous tumorigenesis in a mouse model. Deciphering these mechanisms of RNF8 may shed light on strategies for cancer treatment. In this review, we summarize the current understanding of both classical and nonclassical functions of RNF8, and discuss its roles in the pathogenesis and progression of tumor.

show abstract

“…To identify UBLs that contribute to the etiology of PDA, we queried the TCGA database for UBLs differentially expressed in cancer, including melanoma 27,30 , ovarian cancer 31 , breast cancer [32][33][34] , colorectal cancer 35,36 , lung cancer 37 , and head and neck cancer 36,38 . Of the UBLs that were altered in pancreatic cancer ( Fig S1A) we selected UBLs whose expression may be linked with survival.…”

Section: The Ubiquitin Ligase Rnf125 Is Differentially Expressed In Tmentioning

confidence: 99%

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

Hasnis

Kim

Verma

et al. 2020

Preprint

View full text Add to dashboard Cite

There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens.We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its noncanonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1). Correspondingly, inhibition of RNF125 expression enhanced organoid growth in culture and orthotopic tumor development. Conversely, restoration of PDX1 levels in human or mouse PDA cells and organoids depleted of RNF125, inhibited cell proliferation and growth, while expression of HDAC2 enhanced it. Notably, higher expression of RNF125 and PDX1 coincided with differentiated tumor phenotypes, and better outcome in PDA patients. In demonstrating the importance of RNF125 control of PDX1 expression via HDAC2 ubiquitination in PDA development, our findings highlight markers (RNF125, PDX1) and targets (HDAC2) for monitoring and possible treatment of PDA.

show abstract

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Cited by 32 publications

References 45 publications

RNF8 induces β-catenin-mediated c-Myc expression and promotes colon cancer proliferation

RNF8 induces β-catenin-mediated c-Myc expression and promotes colon cancer proliferation

The Functions of DNA Damage Factor RNF8 in the Pathogenesis and Progression of Cancer

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

Contact Info

Product

Resources

About