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.
authors.affiliation: Department of Biological, Geological and Environmental Sciences, University of Sannio, Benevento, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Sabatino
authors.forename: A
authors.initials: A
authors.lastname: Fucci
authors.forename: M
authors.initials: M
authors.lastname: Pancione
authors.forename: V
authors.initials: V
authors.lastname: Carafa
authors.forename: A
authors.initials: A
authors.lastname: Nebbioso
authors.forename: C
authors.initials: C
authors.lastname: Pistore
authors.forename: F
authors.initials: F
authors.lastname: Babbio
authors.forename: C
authors.initials: C
authors.lastname: Votino
authors.forename: C
authors.initials: C
authors.lastname: Laudanna
authors.forename: M
authors.initials: M
authors.lastname: Ceccarelli
authors.forename: L
authors.initials: L
authors.lastname: Altucci
authors.forename: I M
authors.initials: IM
authors.lastname: Bonapace
authors.forename: V
authors.initials: V
authors.lastname: Colantuoni
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012016:Reference Values; D015203:Reproducibility of Results; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D047495:PPAR gamma; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases