The actions of the PPARγ to regulate target genes are highly
choreographed, being influenced by many factors. This is reflected by the
multiple mechanisms that distort PPARγ signaling in cancer. PPARγ-RXR heterodimer binds to specific
response elements contained within upstream, intronic, and downstream sequences
of target genes. The ability of this heterodimer to participate in either
transactivation or transrepression is disrupted by multiple mechanisms in
cancer cells. (1) Genetic mechanisms; although
relatively rare, mutations to the PPARG gene occur, as do cytogenetic rearrangements, notably in thyroid cancer with
the generation of the PAX-8-PPARγ fusion product. (2) Epigenetic mechanisms; the PPARγ receptor normally exists in a dynamic
equilibrium with each of two large complexes, namely, coactivator (CoA) and
corepressor (CoR) complexes to regulate genes targets. Central components of
these complexes are a cohort of ancillary proteins that act to regulate a
cohort of posttranslational modifications (PTMs) to histone tails and thereby
determine local chromatin organization. In cancer, the stochiometry of this
equilibrium is disrupted with downregulation of CoA components such as PGC1-α and upregulation of CoR components such
as NCOR1. The net result is the distortion of gene regulation abilities, most
likely in a promoter specific manner. (3) Posttranslational mechanisms; PPARγ is regulated by a number of
posttranslational modification including sumoylation, which can allow the
liganded receptor to retain associations with the CoR complex and bring about
ligand-dependent transrepression. The enzymes responsible for this activity
appear altered in malignancy suggesting that the levels of sumoylated PPARγ are in turn distorted. In parallel,
associated cofactors, such as PBP/Med1, are also regulated by PTMs and further
manipulate and PPARγ signaling. (4) Nuclear receptor network dynamics; the PPARγ is a member of a highly interactive
network of receptors and in malignancy these interactions appear distorted. For
example, the ERα (E) homodimer is able to repress the PPARG promoter, and equally PPARγ is both coexpressed with, and regulates
expression of other receptors such as PPARα, LXRs, FXR, and VDR to coordinate
transcriptional programs. (5) Ligand
generation; PPARγ senses a wide panel of lipophilic
ligands many of which are derived from and catabolized downstream of metabolism
of arachidonic acid. Key steps include generation of fatty acids, which are PPARγ ligands, through lipooxygenase (LO)
activity (e.g., 5-LO). To counterbalance these activities, the generation of
prostaglandins is mediated in large part through the actions of cyclooxygenase
(COX) activity (e.g., COX-2). While this can also give rise to PPARγ ligands, these effects are protected
further by the clearance of potent prostaglandin PPARγ ligands by the actions of enzymes, such
as AKR1C3. In malignancy, an inversion of COX-2 to 5-LO occurs, and further
protection from generation of potent prostaglandin ligands occurs, for example,
through upregulation of AKR1C3. (6) Dominant
transcriptional programs; the actions of the PPARγ appear to be distorted as a consequence
of deregulated dominant transcriptional programs, such as Wnt signaling. These
effects are mediated by enhanced β-catenin (β) levels and include sequestration of PPARγ to β-catenin responsive genomic regions.
Implicit within this is that there is a high degree of plasticity of PPARγ signaling and that transcriptional
signals can be placed within a quantifiable hierarchy.
