In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. SY26-03-SY26-03
Abstract:
Cellular decision-making involves integration of inputs from multiple signaling pathways, including tumor suppressor pathways. It is, therefore, of interest to elucidate how tumor suppressor pathways talk with each other to coordinate their activities in normal cells, and whether and how this coordination is perturbed in cancer. To that end, we have been investigating the crosstalk between two pivotal tumor suppressor pathways: the extensively studied p53 pathway and the Hippo pathway, whose relevance to cancer is becoming increasingly appreciated. In mammalian cells, two of the key members of the Hippo pathway are the LATS1 and LATS2 protein kinases. In earlier studies, we found that LATS2 binds to MDM2, the major negative regulator of p53, and inhibits MDM2's E3 ubiquitin ligase activity. Consequently, the binding of LATS2 to MDM2 leads to stabilization p53. The LATS2-MDM2 axis contributes to the activation of p53 in a number of biological stress-response settings, particularly in the context of mitotic machinery dysfunction as well as upon excessive activity of some oncogenes (e.g. H-Ras and K-Ras), where LATS2 undergoes extensive nuclear translocation with a consequent increase in its association with MDM2. Interestingly, the LATS2 gene itself is a bona fide transcriptional target of p53, but its induction by p53 is observed only under particular conditions, most notably those that involve p53 activation via the LATS2-MDM2 axis. These findings position LATS2 in the interface between the p53 and Hippo pathways, and suggest that it may play a role in coordinating the output of those two tumor suppressor pathways in response to stress. We next wished to determine whether the Hippo pathway impacts p53 activity also under nonstressed conditions. To that end, we silenced simultaneously LATS1 and LATS2 in nontransformed MCF10A human mammary epithelial cells. Although LATS downregulation did not affect p53 protein levels, it led to a change in its phosphorylation pattern, particularly a reduction in p53 phosphorylation on serines 15 and 315. Concomitantly, a fraction of the p53 molecules assumed a mutant-like conformation, reflected by increased reactivity with the mutant-specific PAb240 antibody. Remarkably, although p53 did not affect the migratory properties of control MCF10A cells, it turned into a positive regulator of cell migration in LATS-depleted cells. Indeed, RNA-seq analysis revealed that in such cells p53 acquired an increased ability to modulate the expression of genes that are implicated in regulation of cell motility. Of particular note, the genes upregulated by p53 in LATS-silenced cells displayed a significant overlap with genes reported to be upregulated by gain-of-function mutant p53 in breast cancer cells. Interestingly, one of the genes whose expression was selectively upregulated by p53 in LATS-depleted cells was PTGS2, better known as COX2. Moreover, PTGS2 upregulation was found to contribute to the migratory features of such cells, and PTGS2 depletion could mimic to some extent the impact of p53 depletion on migration. In an attempt to understand the molecular basis for the transcriptional rewiring of the “altered” p53 in LATS-depleted cells, we sought to identify proteins that associate preferentially with p53 in cells where LATS expression has been silenced. One of the top hits was the p52 subunit of NF-κB. Furthermore, we found that p52 contributed to the upregulation of PTGS2 in cells harboring the “altered” p53. Together, these findings imply that LATS proteins play an active role in maintaining wild-type p53 in its canonical state, ensuring that it is preferentially dedicated to the transcriptional regulation of canonical wild-type p53 target genes. Once LATS activity is compromised, as occurs in some cancers as a consequence of epigenetic silencing of LATS1 and/or LATS2, part of the p53 population shifts to a mutant-like state, potentially favoring the activation of genes that contribute to cancer rather than suppressing it. Hence, optimal performance of key players in one tumor suppressor pathway (the Hippo pathway) is required in order to sustain optimal performance of another tumor suppressor pathway (the p53 pathway). It seems highly plausible that this tumor suppressor crosstalk is not restricted to LATS kinases only, and input from additional tumor suppressor pathways may potentially also serve to keep p53 in a fully competent tumor suppressive state. Conversely, when such “support group” tumor suppressor pathways are rendered dysfunctional in some cancer cells, this may enable the endogenous wild type to acquire mutant-like properties without the need to accrue real genetic mutations in the TP53 locus. Further identification of such pathways and elucidation of the mechanisms by which they bolster the canonical biochemical features of p53 may provide clues for new strategies to restore tumor suppressive p53 function in cancers that retain a wild type TP53 gene. [N. Furth and N. Bossel Ben-Moshe contributed equally to this work.] Citation Format: Moshe Oren, Noa Furth, Noa Bossel Ben-Moshe, Ziv Porat, Eytan Domany, Yair Pozniak, Tamar Geiger, Yael Aylon. Tumor suppressor crosstalk: Modulation of p53 activity by the Hippo pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY26-03.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-SY26-03
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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