The tumor suppressor phosphatase and tensin homolog protein (PTEN) is negatively regulated by NF-κb p50 homodimers and involves histone 3 methylation/deacetylation in UROtsa cells chronically exposed to monomethylarsonous acid

Abstract

UROtsa cells have been accepted as a model to study carcinogenicity mechanisms of arsenic-associated human bladder cancer. In vitro continuous exposure to monomethylarsonous acid (MMA), leads UROtsa cells to commit to malignant transformation. In this process, NF-κβ-associated inflammatory response seems to play an important role since this transcription factor activates some minutes after cells are exposed in vitro to MMA and keeps activated during the cellular malignant transformation. It is known that a slight decrease in the protein phosphatase and tensin homologue (PTEN) gene expression is enough for some cells to become malignantly transformed. Interestingly, this tumor suppressor has been proven to be negatively regulated by NF-κβ through binding to its gene promoter. Based on these observations we propose that NF-κβ may be involved in arsenic associated carcinogenesis through the negative regulation of PTEN gene expression. Changes in PTEN expression and the binding of p50 NF-κβ subunit to PTEN promoter were evaluated in UROtsa cells exposed for 4, 12, 20, or 24 wk to 50nM MMA. Results showed that MMA induced a significant decrease in PTEN expression around 20 wk exposure to MMA,which correlated with increased binding of p50 subunit to the PTEN promoter. Consistent with these results, ChIP assays also showed a significant decrease in H3 acetylation (H3ac) but an increase in the repression marks H3k9me3 and H327me3 in PTEN promoter when compared with not treated cells. These results suggest that the activation of NF-κβ by MMA may participate in UROtsa cells malignant transformation through the negative regulation of PTEN expression involving p50 homodimers-mediated chromatin remodeling around the PTEN promoter.

USP13 functions as a tumor suppressor by blocking the NF-kB-mediated PTEN downregulation in human bladder cancer

“…Interestingly, a recent study using the immortalized cell line of human urothelial cells (UROtsa), a well-established model to study carcinogenesis mechanisms of human bladder cancer, revealed that monomethylarsonous acid (MMAIII)-induced NF-kB activation modulates PTEN expression. Moreover, NF-kB subunit p50 binding to PTEN promoter is associated with decreased PTEN expression [39]. Our current work further enriches the regulatory network of NF-kB signaling for the post-transcriptional modulation of PTEN (Fig.…”

MiR-342-3p inhibits LCSC oncogenicity and cell stemness through HDAC7/PTEN axis

“…Existing evidence also showed that PTEN is a potent tumor suppressor and down-regulated PTEN enhances cell proliferation and invasion in liver cancer [25]. Previous study also revealed that PTEN is correlated with histone modifications [16,17]. A study performed in breast cancer stem cells provides the evidence that HDAC7 can regulate histone 3 lysine 27 acetylation [13].…”

“…Previous study has reported that PTEN is involved in the progression of liver cancer and might be involved in the stemness of cancer stem cells [14,15]. Several studies have provided evidence that PTEN is correlated with histone modifications [16,17]. However, the roles of miR-342-3p, HDAC7 and PTEN in LCSC remain unclear.…”

Plasmatic membrane toll-like receptor expressions in human astrocytomas

“…In B cells, the absence of PTEN showed an increased in NF-κB activity after TLR4 stimulation [ 56 ]. Additionally NF-κB negatively regulate PTEN [ 57 , 58 ]. Accordingly, in the classical subtype, loss of PTEN may also be implicated in tumor cell proliferation through TLR canonical activation ( Fig 5 ).…”