UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

L. Sabatino, A. Fucci, M. Pancione, V. Carafa, A. Nebbioso, C. Pistore, F. Babbio, C. Votino, C. Laudanna, Michele Ceccarelli, L. Altucci, I. M. Bonapace, V. Colantuoni

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

Original languageEnglish
Pages (from-to)5061-5072
Number of pages12
JournalOncogene
Volume31
Issue number49
DOIs
Publication statusPublished - 6 Dec 2012
Externally publishedYes

Fingerprint

PPAR gamma
Epigenomics
Colorectal Neoplasms
Histone Code
Foster Home Care
Epithelial-Mesenchymal Transition
Gene Silencing
DNA Methylation
Tumor Suppressor Genes
Phenotype

Keywords

  • colorectal cancer prognosis
  • epigenetics
  • PPARG
  • UHRF1

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Sabatino, L., Fucci, A., Pancione, M., Carafa, V., Nebbioso, A., Pistore, C., ... Colantuoni, V. (2012). UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. Oncogene, 31(49), 5061-5072. https://doi.org/10.1038/onc.2012.3

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. / Sabatino, L.; Fucci, A.; Pancione, M.; Carafa, V.; Nebbioso, A.; Pistore, C.; Babbio, F.; Votino, C.; Laudanna, C.; Ceccarelli, Michele; Altucci, L.; Bonapace, I. M.; Colantuoni, V.

In: Oncogene, Vol. 31, No. 49, 06.12.2012, p. 5061-5072.

Research output: Contribution to journalArticle

Sabatino, L, Fucci, A, Pancione, M, Carafa, V, Nebbioso, A, Pistore, C, Babbio, F, Votino, C, Laudanna, C, Ceccarelli, M, Altucci, L, Bonapace, IM & Colantuoni, V 2012, 'UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression', Oncogene, vol. 31, no. 49, pp. 5061-5072. https://doi.org/10.1038/onc.2012.3
Sabatino, L. ; Fucci, A. ; Pancione, M. ; Carafa, V. ; Nebbioso, A. ; Pistore, C. ; Babbio, F. ; Votino, C. ; Laudanna, C. ; Ceccarelli, Michele ; Altucci, L. ; Bonapace, I. M. ; Colantuoni, V. / UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression. In: Oncogene. 2012 ; Vol. 31, No. 49. pp. 5061-5072.
@article{d4234acb0c0144f2947d00c38e981e52,
title = "UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression",
abstract = "Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.",
keywords = "colorectal cancer prognosis, epigenetics, PPARG, UHRF1",
author = "L. Sabatino and A. Fucci and M. Pancione and V. Carafa and A. Nebbioso and C. Pistore and F. Babbio and C. Votino and C. Laudanna and Michele Ceccarelli and L. Altucci and Bonapace, {I. M.} and V. Colantuoni",
year = "2012",
month = "12",
day = "6",
doi = "10.1038/onc.2012.3",
language = "English",
volume = "31",
pages = "5061--5072",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "49",

}

TY - JOUR

T1 - UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression

AU - Sabatino, L.

AU - Fucci, A.

AU - Pancione, M.

AU - Carafa, V.

AU - Nebbioso, A.

AU - Pistore, C.

AU - Babbio, F.

AU - Votino, C.

AU - Laudanna, C.

AU - Ceccarelli, Michele

AU - Altucci, L.

AU - Bonapace, I. M.

AU - Colantuoni, V.

PY - 2012/12/6

Y1 - 2012/12/6

N2 - Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

AB - Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

KW - colorectal cancer prognosis

KW - epigenetics

KW - PPARG

KW - UHRF1

UR - http://www.scopus.com/inward/record.url?scp=84870821482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870821482&partnerID=8YFLogxK

U2 - 10.1038/onc.2012.3

DO - 10.1038/onc.2012.3

M3 - Article

VL - 31

SP - 5061

EP - 5072

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 49

ER -