High Expression of the Resistant Factor YY1 and Low Expression of the RKIP Chemosensitizing Factor in Multiple Myeloma: Delineation of Several Crosstalk Pathways That Regulate the Expression of These Factors

Background: We have reported that multiple myeloma (MM) expresses high levels of the transcription (oncogenic) factor YY1, which regulates cell survival, proliferation, and resistance to both immuno- and chemotherapeutic drugs.¹ Inhibition of YY1 sensitizes the tumor cells to cell death/apoptosis to cytotoxic drugs. In contrast, we have also reported that MM expresses very low levels of Raf kinase inhibitor protein (RKIP) and/or high levels of inactive phosphorylated RKIP.² Overexpression of RKIP or de-phosphorylation of phosphorylated RKIP sensitized drug-resistant MM to drug-induced apoptosis

Hypothesis: The inverse relationship between YY1 and RKIP expression levels suggested that the two factors may be regulated through crosstalk pathways.

Methods: Analysis of the literature revealed the presence of five crosstalk pathways that link RKIP and YY1.

Results: The crosstalks consisted of the followings: (1) The NF-κB/YY1/Snail/RKIP loop. In the presence of RKIP, the NF-κB pathway is inhibited and consequently, the NF-κB targets YY1 and Snail are also inhibited. In turn, inhibition of the RKIP repressor Snail resulted in the upregulation of RKIP expression, all of which led to sensitization of drug-resistant tumor cells. (2) The p38 MAPK/RKIP/GSK3β/Snail/YY1 loop. In the presence of RKIP expression, the p38 MAPK-mediated phosphorylation of GSK3β is inhibited and results in the phosphorylation of Snail and its degradation, leading to the de-repression of RKIP expression and inhibition of YY1. (3) The RKIP/Smurf-2/YY1/Snail loop. SMAD ubiquitin regulatory factor 2 (Smurf-2) is an E3 ubiquitin ligase that degrades YY1. In tumor cells, there is low expression of Smurf-2 and, thus, little inhibition of YY1 with high Snail expression in the presence of low expression of RKIP. In the presence of high levels of Smurf-2, YY1 is inhibited, resulting in the inhibition of Snail and de-repression of RKIP. (4) The RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1 loop. Let-7/miR98 suppresses Ras and inhibits the MAPK signaling pathway. In the absence of RKIP, the Raf/MEK1-2 pathway is activated and downstream Myc is expressed. In turn, Myc-induced Lin-28 inhibits Let-7, and leads to upregulation of HMGA2. Consequently, HMGA2 activates Snail, in addition to its regulation by YY1. In contrast, in the presence of RKIP, the Raf/MEK pathway is inhibited and there is downstream inhibition of its targets Myc, Lin-28, and HMGA2, leading to an inhibition of Snail and de-repression of RKIP. (5) The RKIP/GPCR/STAT3/miR-34/YY1 loop. In tumor cells expressing low levels of RKIP, there is no efficient inhibition of GPCR and MAKP signaling pathways. Hence, there is a constitutive activation of oncogenic STAT3 that inhibits the tumor suppressor miR-34. Thus, low miR-34 levels de-repress YY1 translation and facilitate its effects on the survival and the resistance of tumor cells to cytotoxic drugs.

Conclusion and Implications: The above YY1/RKIP gene signatures might predict the tumor expanding potential and overall aggressiveness and their detriments that contribute to tumor regression. Targeting YY1 inhibition or RKIP induction via interference of the above crosstalk pathways may result in synergistic activity in combination with conventional treatments.

References

¹ Bonavida B, Kaufhold S. Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: a therapeutic target. Pharmacol Ther. 150:149-68, 2015.

² Baritaki, S, Huerta-Yepez, S, Cabrava-Haimandez, M, Sensi, M, Canevari, S, Libra, M, Penichet, M, Chen, H, Berenson, JR, Bonavida, B. Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma. Forum on Immunopathological Diseases and Therapeutics, 2: 179-188, 2011.