Miz-1 and Max compete to engage c-Myc: implication for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1

Abstract

c-Myc is a basic helix-loop-helix leucine zipper (b-HLH-LZ) transcription factor deregulated in the majority of human cancers. As a heterodimer with Max, another b-HLH-LZ transcription factor, deregulated and persistent c-Myc accumulates at transcriptionally active promoters and enhancers and amplifies transcription. This leads to the so-called transcriptional addiction of tumor cells. Recent studies have showed that c-Myc transcriptional activities can be reversed by its association with Miz-1, a POZ transcription factor containing 13 classical zinc fingers. Although evidences have led to suggest that c-Myc interacts with both Miz-1 and Max to form a ternary repressive complex, earlier evidences also suggest that Miz-1 and Max may compete to engage c-Myc. In such a scenario, the Miz-1/c-Myc complex would be the entity responsible for the inhibition of c-Myc transcriptional amplification. Considering the implications of the Miz-1/c-Myc interaction, it is highly important to solve this duality. While two potential c-Myc interacting domains (hereafter termed MID) have been identified in Miz-1 by yeast two-hybrid, with the b-HLH-LZ as a bait, the biophysical characterization of these interactions has not been reported so far. Here, we report that the MID located between the 12th and 13th zinc finger of Miz-1 and the b-HLH-LZ of Max compete to form a complex with the b-HLH-LZ of c-Myc. Our results support the notion that the repressive action of Miz-1 on c-Myc does not rely on the formation of a ternary complex. The implications of these observations for the mechanism of inhibition of c-Myc transcriptional activity by Miz-1 are discussed. Proteins 2017; 85:199-206. © 2016 Wiley Periodicals, Inc.

Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy

“…Recent research suggested that the transcriptional activities of c-Myc can be reversed once associated with Miz-1. Miz-1 competes with Max to form a complex with c-Myc through the b-HLH-LZ domain (between 12th and 13th zinc finger) ( Bédard et al, 2017 ). Miz-1 can interact with zinc-finger (ZF) transcriptional repressor growth factor independence 1 (Gfi-1) and Myc, form a ternary complex at the cyclin dependent kinase inhibitor (CDKN) promoter (including CDKN1A and CDKN2B), and repress CDKN synergistically ( Basu et al, 2009 ; Liu et al, 2010 ; Aesoy et al, 2014 ).…”

Therapeutic targeting of “undruggable” MYC

“… 115 , 117 Due to the profound functional implication of the MYC/MIZ1 interaction on MYC activity, fostering this association via small molecule inhibition of HUWE1 has been explored as a therapy. 113 , 115 , 116 , 118 , 119 The small compounds BI8622 and BI8626 are specific inhibitors of HUWE1 that enhance MYC proteolysis and suppress MYC-dependent transactivation resulting in inhibition of cell growth in colon carcinoma and multiple myeloma. 116 , 120 In vivo , HUWE1 knock-down clearly reduces tumor burden, but both BI8622 and BI8626 have suboptimal pharmacokinetics that prevents the assessment of their in vivo efficacy in MYC-driven tumor models.…”

Collaborating single-cell and bulk RNA sequencing for comprehensive characterization of the intratumor heterogeneity and prognostic model development for bladder cancer

“…The canonical role of MYC is to act as a transcriptional regulator in a dimeric DNA-binding complex with MAX [ 20 ]. Although MYC-MAX dimers generally stimulate transcription, MYC can also repress target genes via association with the zinc-finger transcription factor Miz-1 [ 21 ]. While the number of transcriptionally activated target genes of MYC is substantial, many transcriptionally repressed targets have also been identified.…”