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.

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…In addition, it stimulates E-cadherin gene transcription, further supporting the anti-metastatic activity of this compound [8]. These results are consistent with the data from literature disclosing for PPARc a protective role in in vitro and in vivo colorectal cancer (CRC) models [9][10][11][12][13]. In the gastrointestinal tract, in fact, PPARc impairs cellular proliferation, stimulates differentiation and induces apoptosis [14].…”

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

“…62 Similarly, alterations in the methylation of peroxisome proliferatoractivated receptor (PPARγ) due to UHRF1-mediated DNMT3b recruitment on its promoter region resulted in progression of colorectal cancer. 63 In bladder cancer cells, UHRF1 suppressed regulator of G-protein signaling 2 (RGS2) gene expression via promoter hypermethylation resulting in cellular proliferation. 64 Role of UHRF1 in carcinogenesis was also supported by the observation that its downregulation in MKN45 Catalyzes di-/tri-methylation of H3 at lysine 9 which represses the transcription of its target genes Kim et al 1 …”

Negative Regulation of the Acetyltransferase TIP60-p53 Interplay by UHRF1 (Ubiquitin-like with PHD and RING Finger Domains 1)

“…Recently UHRF1 overexpression has been linked to tumor progression and poor prognosis in prostate cancer and colorectal cancer (37,38). UHRF1 function in heterochromatin formation and inheritance of genomic DNA methylation patterns has long been implicated as its major oncogenic role.…”

“…Recent studies demonstrated correlation of UHRF1 overexpression with tumor growth and aggressiveness and poor prognosis in prostate cancer and colorectal cancer (37,38). The oncogenic role of UHRF1 has long been implicated through epigenetic regulation, however recent indication of coexistence of UHRF1 in the same multi-protein complex with the TIP60 acetyltransferase (16,17) that modulates p53-dependent growth arrest and apoptosis leads to the attractive hypothesis that UHRF1 may be linked to the TIP60-p53 interplay and modulate the p53-dependent damage response pathway.…”