Gene array analysis reveals a common Runx transcriptional programme controlling cell adhesion and survival

Abstract

The Runx genes are important in development and cancer, where they can act either as oncogenes or tumour suppressors. We compared the effects of ectopic Runx expression in established fibroblasts, where all three genes produce an indistinguishable phenotype entailing epithelioid morphology and increased cell survival under stress conditions. Gene array analysis revealed a strongly overlapping transcriptional signature, with no examples of opposing regulation of the same target gene. A common set of 50 highly regulated genes was identified after further filtering on regulation by inducible RUNX1-ER. This set revealed a strong bias toward genes with annotated roles in cancer and development, and a preponderance of targets encoding extracellular or surface proteins, reflecting the marked effects of Runx on cell adhesion. Furthermore, in silico prediction of resistance to glucocorticoid growth inhibition was confirmed in fibroblasts and lymphoid cells expressing ectopic Runx. The effects of fibroblast expression of common RUNX1 fusion oncoproteins (RUNX1-ETO, TEL-RUNX1 and CBFB-MYH11) were also tested. Although two direct Runx activation target genes were repressed (Ncam1 and Rgc32), the fusion proteins appeared to disrupt the regulation of downregulated targets (Cebpd, Id2 and Rgs2) rather than impose constitutive repression. These results elucidate the oncogenic potential of the Runx family and reveal novel targets for therapeutic inhibition.

Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts

“…This assumption is further supported by the specific expression signature of E/R-positive leukemias, which also suggests the involvement of other PI3K/AKT/mTOR-regulated processes, including above all cell adhesion and DNA damage response. 15,37 Pharmacological inhibition of the aberrantly activated PI3K/AKT/mTOR pathway has emerged as one of the therapeutic options for overcoming drug resistance. 13 Although E/R-positive leukemias are in general highly treatment-sensitive at initial presentation, a substantial proportion of them apparently become drug-resistant when they relapse.…”

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…The RUNX genes are widely expressed, but show differential, tissue-specific expression. Although their strong homology indicates a certain degree of redundancy as observed during mouse embryogenesis (Fukushima-Nakase et al, 2005) and transcription regulation of various genes (for example Sgpp1, Ncam1, p21 WAF1 ) (Wotton et al, 2008), the RUNX proteins have been shown to perform distinct functions that are dependent on tissue type ). This review explores the dualistic associations of RUNX3 with cancer with emphasis on the emerging concept of RUNX3 as a multifunctional suppressor of solid tumors.…”

The role of nuclear organization in cancer

“…RUNX (runt-transcription factor) transcription factors regulate genes involved in growth, survival and differentiation [103]. RUNX1 is involved in haematopoesis, RUNX2 in skeletal development, and RUNX3 in neurogenesis and gut development (reviewed in [104][105][106]).…”