Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer

Abstract

We have recently demonstrated that the transcription factor MYB can modulate several cancer-associated phenotypes in pancreatic cancer. In order to understand the molecular basis of these MYB-associated changes, we conducted deep-sequencing of transcriptome of MYB-overexpressing and -silenced pancreatic cancer cells, followed by in silico pathway analysis. We identified significant modulation of 774 genes upon MYB-silencing (p < 0.05) that were assigned to 25 gene networks by in silico analysis. Further analyses placed genes in our RNA sequencing-generated dataset to several canonical signalling pathways, such as cell-cycle control, DNA-damage and -repair responses, p53 and HIF1α. Importantly, we observed downregulation of the pancreatic adenocarcinoma signaling pathway in MYB-silenced pancreatic cancer cells exhibiting suppression of EGFR and NF-κB. Decreased expression of EGFR and RELA was validated by both qPCR and immunoblotting and they were both shown to be under direct transcriptional control of MYB. These observations were further confirmed in a converse approach wherein MYB was overexpressed ectopically in a MYB-null pancreatic cancer cell line. Our findings thus suggest that MYB potentially regulates growth and genomic stability of pancreatic cancer cells via targeting complex gene networks and signaling pathways. Further in-depth functional studies are warranted to fully understand MYB signaling in pancreatic cancer.

Substitution of Thr572 to Ala in mouse c-Myb attenuates progression of early erythroid differentiation

“…Genome-wide studies have identified numerous genes as targets of c-Myb 37,38 ; therefore, the importance of c-Myb in development, cell survival, proliferation, and homeostasis is unequivocal 7 . However, it is not yet clear what type of transcriptional regulation is lost as a critical event resulting from c-Myb reduction during progenitor differentiation.…”

Regulation of MYB mediated cisplatin resistance of ovarian cancer cells involves miR-21-wnt signaling axis

“…Moreover, the expression of c-MYB correlated with higher grade ovarian cancer which suggested a direct relationship between c-MYB expression and aggressive ovarian cancer. The oncogenic role of c-MYB is not limited to ovarian cancer and has been reported in hematological malignancies as well as several solid tumors [9][10][11][12][13] , Despite such wealth of information regarding the oncogenic potential of c-MYB, its role in cisplatin resistance was not known prior to this report 9 . The study reported a connection between c-MYB expression and acquired cisplatin resistance, but there is still no clear understanding regarding how c-MYB can influence cisplatin resistance.…”

Cancer Chemoprevention by Phytochemicals: Nature’s Healing Touch

“…IL-6 levels can be reduced by EGCG in breast cancer TME, as part of regulation of tumor-associated macrophages (TAMs) [ 114 ], and IL-18 can be inhibited by resveratrol in melanoma TME, leading to reduced metastasis [ 115 ]. Also, plumbagin has been demonstrated to inhibit the activity of c-MYB [ 116 ], an important modulator of tumor-stromal cross-talk and pancreatic cancer signaling [ 117 ]. In addition, EGCG has been shown to inhibit prostate cancer-associated myofibroblast differentiation [ 118 ].…”