Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

Abstract

The Myc bHLH-ZIP transcription factor is deregulated by most cancers. As a heterodimer with the bHLH-ZIP protein Max, Myc regulates target genes that contribute to metabolism and proliferation. This “Myc Network” cross-talks with the “Mlx Network” comprised of the Myc-like bHLH-ZIP proteins MondoA and ChREBP and the Max-like bHLH-ZIP protein Mlx. This “Extended Myc Network” regulates genes with both common and distinct functions. We have generated hepatocytes lacking Mlx (mlxKO) or Mlx+Myc (double KO or DKO) and quantified their abilities to replace dying hepatocytes in a murine model of Type I tyosinemia. We find that this function deteriorates as the Extended Myc Network is progressively dismantled. Genes dysregulated in mlxKO and DKO hepatocytes include those involved in translation and mitochondrial function. The Myc and Mlx Networks thus cross-talk with the latter playing a disproportionate role. mycKO and mlxKO mice also develop non-alcoholic fatty liver disease and mlxKO and DKO mice develop extensive hepatic adenomatosis not observed in wild-type, mycKO, chrebpKO or mycKOxchrebpKO mice. In addition to demonstrating cooperation between the Myc and Mlx Networks, this study reveals the latter to be more important in maintaining metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.

Normal and Neoplastic Growth Suppression by The Extended Myc Network

“…A more recent study of Mga function in cancer that expanded upon the above results indicated that CRISPR-mediated Mga inactivation accelerated tumor growth and shortened survival in both the KrasLSL-G12D and KrasLSL-G12D+Tp53-/models of lung cancer [335,337]. While this indicated that Mga loss facilitated the growth of tumors in highly susceptible hosts, it was not determined whether Mga inactivation in otherwise normal mice impacted spontaneous tumor growth as happens with more traditional TSs such as TP53 or Mlx [63,[352][353][354].…”

“…Moreover, ChREBP can also bind to single E-boxes and can do so in a glucose-independent manner [59][60][61]. The fact that Myc can also bind the double Eboxes of the ChoRE suggests that shared gene targets may allow for transcriptional promiscuity and additional levels of cross-talk among members of the Extended Myc Network [63].…”

“…Yet, the recurrent loss of Max in pheochromoctytomas, parganglioneuromas and several other tumors supports its role as a potent TS [106][107][108][109][110][111][112]. Similarly, MLX loss dramatically impairs normal hepatocyte proliferation while at the same time serving as a potent suppressor of benign hepatic adenomatosis [63].…”

“…1). Both E-boxes and ChoREs, but particularly the latter, can be quite variable and cross-binding of one Network's members to the other Network's sites is likely more common than previously appreciated [35,[58][59][60][61][62][63]. Binding by ChREBP may also facilitate promiscuous, non-E-box-dependent binding by Myc at nearby sites [64].…”

“…Mlx Network target genes, while overlapping with those regulated by the Myc Network, are both fewer in number and have been reported to be more functionally restricted [65][66][67]. They tend to encode enzymes involved in carbohydrate and lipid metabolism; mitochondrial and ribosomal proteins and factors that regulate translational initiation, elongation and termination [21,33,50,[57][58][59][60]63,[65][66][67][68][69][70][71][72][73][74][75][76][77][78]. Together these findings indicate that, via selective, cytoplasmic-nuclear partitioning, sharing of Mxd1,4 and Mnt and binding to both common and unique target genes, this "Extended Myc Network" cross-talks, while simultaneously communicating with and responding to the metabolic cues needed to support energy-intensive processes such as translation and proliferation [43,[50][51][52]56,[77][78][79][80][81][82][83][84][85].…”