CTCF and BORIS Regulate Rb2/p130 Gene Transcription: A Novel Mechanism and a New Paradigm for Understanding the Biology of Lung Cancer

Abstract

Although innumerable investigations regarding the biology of lung cancer have been carried out, many aspects thereof remain to be addressed, including the role played by the retinoblastoma-related protein Rb2/ p130 during the evolution of this disease. Here we report novel findings on the mechanisms that control Rb2/ p130 gene expression in lung fibroblasts and characterize the effects of Rb2/p130 deregulation on the proliferative features of lung cancer cells. We revealed for the first time that in lung fibroblasts the expression of Rb2/p130 gene is directly controlled by the chromatin insulator CCCTC-binding factor, CTCF, which by binding to the Rb2/p130 gene promoter induces, and/or maintains, a specific local chromatin organization that in turn governs the transcriptional activity of Rb2/p130 gene. However, in lung cancer cells the activity of CTCF in controlling Rb2/p130 gene expression is impaired by BORIS, a CTCF-paralogue, which by binding to the Rb2/p130 gene could trigger changes in the chromatin asset established by CTCF, thereby affecting CTCF regulatory activity on Rb2/p130 transcription. These studies not only provide essential basic insights into the molecular mechanisms that control Rb2/p130 gene expression in lung cancer, but also offer a potential paradigm for the actions of other activators and/or corepressors, such as CTCF and BORIS, that could be crucial in explaining how alterations in the mechanism regulating Rb2/p130 gene expression may accelerate the progression of lung tumors, or favor the onset of recurrence after cancer treatment. Mol Cancer Res; 9(2); 225-33. Ó2011 AACR.

Integrating role of T antigen, Rb2/p130, CTCF and BORIS in mediating non-canonical endoplasmic reticulum-dependent death pathways triggered by chronic ER stress in mouse medulloblastoma

“…We investigated if glucose deprivation may influence and regulate the transcription of this gene in lung cancer cells. 8 To assess whether Rb2/p130 gene transcription is regulated in mouse medulloblastoma cells by direct binding of CTCF/BORIS to Rb2/p130 promoter, we performed crosslinking chromatin immunoprecipitation (XChIP) assay using CTCF or BORIS as immunoprecipitating antibodies. PCRs were performed using primers to amplify a specific region of RB2/p130 promoter.…”

“…7 Interestingly, we recently reported that CTCF and BORIS directly regulate Rb2/p130 gene transcription in lung cancer and suggested a novel role for Rb2/p130 in the mechanisms used by cancer cells in evading senescence and apoptosis and promoting accelerated cell proliferation. 8 Caspase-12 is a member of the caspase family of intracellular cysteine proteases and was first identified in mice. 9 It has been shown that Caspase-12 is localized in the endoplasmic reticulum (ER) and activated by ER stress.…”

Early Targets of miR-34a in Neuroblastoma

“…Various studies have shown that CTCF is involved in cell cycle arrest, apoptosis, and differentiation, indicating that it is a potential tumor-suppressor factor. Other studies, however, found that CTCF protein levels are elevated in both breast and lung tumoral cell lines (55,56) and are also associated with apoptosis resistance (55). These controversial results can be explained by the role of CTCF as a differentiation-inducing factor, involving a variety of signaling pathways depending on its cellular context (57)(58)(59).…”

CTCF (CCCTC-binding factor (zinc finger protein))

“…Other methylated CTCF targets were found in the genes AWT1 or WT1-AS in WT (Hancock et al, 2007), Bcl6 in B cell lymphomas (Lai et al, 2010), the miR125b locus in breast cancer (Soto-Reyes et al, 2012), p53, pRb (De La Rosa-Velazquez et al, 2007Davalos-Salas et al, 2011), ARF (Tam et al, 2003;Rodriguez et al, 2010), INK4B, BRCA1 (Butcher et al, 2004;Butcher and Rodenhiser, 2007;Xu et al, 2010) and Rasgrf1 (Yoon et al, 2005). CTCF and its paralogue BORIS regulate pRb in lung cancer (Fiorentino et al, 2011), and CTCF could regulate the response to oestrogen in breast cancer (Zhang et al, 2010). We describe below the rare cases of point mutations affecting the CTCF protein.…”