The Polycomb Group Protein Bmi-1 Is Essential for the Growth of Multiple Myeloma Cells

Abstract

Bmi-1 is a member of the Polycomb group family of proteins that function in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. Bmi-1 was first identified through its ability to accelerate c-Myc-induced lymphomagenesis. Subsequent studies have further supported an oncogenic role for Bmi-1 in several cancers including those of the breast, lung, prostate, and brain. Using a stable and inducible shRNA system to silence Bmi-1 gene expression, we show a novel role for Bmi-1 in regulating the growth and clonogenic capacity of multiple myeloma cells both in vitro and in vivo. Moreover, to elucidate novel gene targets controlled by Bmi-1, global transcriptional profiling studies were performed in the setting of induced loss of Bmi-1 function. We found that the expression of the proapoptotic gene Bim is negatively regulated by Bmi-1 and that Bim knockdown functionally rescues the apoptotic phenotype induced upon loss of Bmi-1. Therefore, these studies not only highlight Bmi-1 as a cancer-dependent factor in multiple myeloma, but also elucidate a novel antiapoptotic mechanism for Bmi-1 function involving the suppression of Bim.

MiR-200b and miR-15b regulate chemotherapy-induced epithelial-mesenchymal transition in human tongue cancer cells by targeting BMI1

“…In this study, we identified miR-200b/miR-15b-BMI1 as another important pathway regulating EMT and chemo-resistance of TSCC cells. This is supported by the fact that BMI1 can render apoptotic resistance by enhancing anti-oxidant response (Crea et al, 2010), activating the IKK-NF-kappaB pathway (Li et al, 2010) or repressing the pro-apoptotic gene Bim (Jagani et al, 2010). Thus EMT in TSCC cells may contribute to drug resistance either through Twist1 or Snail, which MiR-200b and miR-15b in chemotherapy-induced EMT L Sun et al directly controls EMT process, or through BMI1 that is regulated by EMT-associated miRNAs.…”

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

“…40 Notably, Nanog and b-catenin were more highly expressed in SP fraction than in MP fraction of RPMI 8226 cells (Figure 6a). After treatment with C3B3, expression levels of Sox2, Oct3/4, Nanog and b-catenin were significantly suppressed both in SP and MP cells (Figure 6a).…”

Polycomb group proteins and their roles in carcinogenesis

“…bmi1 -/-mice have increased apoptosis in lymphoid tissues, a phenotype that is rescued by depleting p16 INK4A and p14 ARF or by over-expressing the apoptosis inhibitor BCL2 [7]. Loss-of-function analysis of BMI1 using RNA interference (RNAi) in both normal and malignant human cells showed that loss of BMI1 promoted cancer specific cell death, as well as an increased production of cleaved caspase-3 and the increased expression of proapoptotic gene Bim [8]. On the other hand, an S-adenosylhomocysteine hydrolase inhibitor, 3-deazaneplanocin A (DZNep), induces efficient apoptotic cell death in cancer cells but not in normal cells.…”

“…BMI1 and EZH2 have been identified as potential diagnostic and prognostic markers for several cancer types. Targeting PcG proteins is a valid therapeutic strategy because decreased levels of BMI1 and EZH2 induce cancer cell specific apoptosis and inhibit chemoresistance in tumors undergoing PcG protein-induced EMT [8,9]. MicroRNAs (miRNAs) are short ribonucleic acid (RNA) molecules; they are post-transcriptional regulators that bind to complementary sequences on target mRNAs, usually resulting in translational repression and gene silencing.…”