The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression

Yang, Yong; Han, Jeung Whan; Youn, Hong Duk; Cho, Eun Jung

doi:10.1093/nar/gkp991

Cited by 70 publications

(66 citation statements)

References 37 publications

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“…Although Suv39H1 has been mainly associated with repression of pericentromeric heterochromatin, 38 some reports indicate that this enzyme is involved in regulation of euchromatic genes, including CDH1, 39 and other oncosuppressors and oncogenes. 40 Most interestingly, we found that binding of Suv39H1 to gene promoters was reduced in cells depleted of UHRF1, suggesting that UHRF1 was directly involved in the recruitment of Suv39H1. Conversely, Suv39H1 was not needed for binding of UHRF1 to gene promoters.…”

Section: Discussionmentioning

confidence: 71%

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression

et al. 2012

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Epigenetic silencing of tumour suppressor genes is an important mechanism involved in cell transformation and tumour progression. The Set and RING-finger-associated domain-containing protein UHRF1 might be an important link between different epigenetic pathways. Here, we report that UHRF1 is frequently overexpressed in human prostate tumours and has an important role in prostate cancer pathogenesis and progression. Analysis of human prostate cancer samples by microarrays and immunohistochemistry showed increased expression of UHRF1 in about half of the cases. Moreover, UHRF1 expression was associated with reduced overall survival after prostatectomy in patients with organ-confined prostate tumours (Po0.0001). UHRF1 expression was negatively correlated with several tumour suppressor genes and positively with the histone methyltransferase (HMT) EZH2 both in prostate tumours and cell lines. UHRF1 knockdown reduced proliferation, clonogenic capability and anchorage-independent growth of prostate cancer cells. Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. Gene reactivation upon UHRF1 depletion was associated with changes in histone H3K9 methylation, acetylation and DNA methylation, and impaired binding of the H3K9 HMT Suv39H1 to the promoter of silenced genes. Co-immunoprecipitation experiments showed direct interaction between UHRF1 and Suv39H1. Our data support the notion that UHRF1, along with Suv39H1 and DNA methyltransferases, contributes to epigenetic gene silencing in prostate tumours. This could represent a parallel and convergent pathway to the H3K27 methylation catalyzed by EZH2 to synergistically promote inactivation of tumour suppressor genes. Deregulated expression of UHRF1 is involved in the prostate cancer pathogenesis and might represent a useful marker to distinguish indolent cancer from those at high risk of lethal progression.

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Section: Discussionmentioning

confidence: 71%

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression

et al. 2012

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“…In our study, none of the confi rmed CDKN2B mutation carriers were known to have a nonrenal neoplasm, but further studies will defi ne the full range of tumor types associated with CDKN2B mutations. It is interesting to note that germline mutations in CDC73 (cell division cycle 73) predispose to both parathyroid and renal tumors ( 26 ), and the CDC73 gene product (parafi bromin) has been reported to repress cyclin D1 expression and induce cell-cycle arrest ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma

et al. 2015

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Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL , MET , SDHB , FH , FLCN , PTEN , and BAP1 . However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identifi ed a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals ( n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the threedimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affi nity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These fi ndings identify germline CDKN2B mutations as a novel cause of familial RCC. SIGNIFICANCE:Germline loss-of-function CDKN2B mutations were identifi ed in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to infl uence the management of disseminated disease. Cancer Discov; 5(7);

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“…Parafibromin overexpression was documented to induce cell cycle arrest in G1 phase by repressing cyclin D1 via histone H3K9 methylation, indicating that parafibromin has a critical role in cell cycle (Zhang et al, 2006;Yang et al, 2010). Parafibromin or Paf1 knockdown was proved to stimulate cell proliferation and increase the c-myc level by stabilizing c-myc protein and activating the c-myc promoter (Lin et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

Zhao¹,

Sun²,

Zhu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Parafibromin is a protein encoded by the HRPT2 (hyperparathyroidism 2) oncosuppressor gene and its down-regulated expression is involved in pathogenesis of parathyroid, breast, gastric and colorectal carcinomas. This study aimed to clarify the effects of parafibromin expression on the phenotypes and relevant mechanisms of DLD-1 colon carcinoma cells. Methods: DLD-1 cells transfected with a parafibromin-expressing plasmid were subjected to examination of phenotype, including proliferation, differentiation, apoptosis, migration and invasion. Phenotype-related proteins were measured by Western blot. Parafibromin and ki-67 expression was detected by immunohistochemistry on tissue microarrays. Results: The transfectants showed higher proliferation by CCK-8, better differentiation by electron microscopy and ALP activity and more apoptotic resistance to cisplatin by DNA fragmentation than controls. There was no difference in early apoptosis by annexin V, capase-3 activity, migration and invasion between DLD-1 cells and their transfectants. Ectopic parafibromin expression resulted in down-regulated expression of smad4, MEKK, GRP94, GRP78, GSK3β-ser9, and Caspase-9. However, no difference was detectable in caspase-12 and -8 expression. A positive relationship was noted between parafibromin and ki-67 expression in colorectal carcinoma. Conclusions: Parafibromin overexpression could promote cell proliferation, apoptotic resistance, and differentiation of DLD-1 cells.

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The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression

Cited by 70 publications

References 37 publications

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression

The SRA protein UHRF1 promotes epigenetic crosstalks and is involved in prostate cancer progression

Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma

Effects of Parafibromin Expression on the Phenotypes and Relevant Mechanisms in the DLD-1 Colon Carcinoma Cell Line

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