Down-regulation of LATS kinases alters p53 to promote cell migration

Abstract

p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer-associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently down-regulated in breast cancer; we propose that such down-regulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.

p53 shades of Hippo

“…This is reflected by reduced phosphorylation, conformational changes and alteration of transcriptional targets, all of which contribute to a mutant-like phenotype of wt p53. 169 These multiple points of regulatory interactions may also dictate selective forces during tumorigenesis that drive rewiring and alterations of the two pathways. Although the TP53 gene is highly mutated in diverse cancer types, pancancer TCGA data 170 reveal that there are also tumor types with relatively low prevalence of such mutations, for example, kidney renal clear-cell carcinoma 3%; lymphoblastic acute myeloid leukemia (LAML) 8%; glioblastoma multiforme 29%, as opposed to cancers with frequent TP53 mutations (ovarian Cross-talk between the Hippo and p53 signaling pathways N Furth et al carcinoma 83%, lung squamous cell carcinoma 82%, HNSCC 71%).…”

“…36 Both YAP and p53 might embody an inherent capacity to adopt pseudomutant status, which must be coordinated; perhaps by their common upstream regulator, LATS (Figure 4). Interaction of additional elements of the Hippo pathway beyond LATS, 169 might also modulate p53 conformation. In turn, pseudomutant wt p53 might mimic the impact of mutp53 on Hippo pathway function.…”

The Paradox of p53: What, How, and Why?

“…In this way, such tumors may still reap the potential benefits of mutant p53 GOF even in the absence of TP53 gene mutations. Furthermore, some cancer-associated deregulated signaling pathways may force genetically WT-p53 to adopt "pseudomutant" properties, bypassing the selective pressure for TP53 mutations (Furth et al 2015). However, when the signaling landscape of such cancer cells is profoundly altered (e.g., on exposure to acute stress), the canonical WT conformation of their p53 might be restored, reinstating a canonical p53 transcriptional program.…”

Roles of Large Tumor Suppressor Genes in Breast Cancer.

“…Therefore, 956 LATS 1/2 regulate mammary cell proliferation and maturation through antagonism of YAP/TAZ. The down regulation of LATS kinases also alters P53, a tumor suppressor/regulator of homeostasis, to promote cell migration which thereby can lead to metastasis to other organs [24]. Mutation of tumor suppressor genes, loses its capabilities and acquire gain of function to enhance tumorigenesis and invasion.…”