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mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression
and tumor growth in glioblastoma
#MMPMID29059166
Holmes B
; Benavides-Serrato A
; Freeman RS
; Landon KA
; Bashir T
; Nishimura RN
; Gera J
Oncogene
2018[Feb]; 37
(6
): 732-743
PMID29059166
show ga
Overexpression of Rictor has been demonstrated to result in increased mechanistic
target of rapamycin C2 (mTORC2) nucleation and activity leading to tumor growth
and increased invasive characteristics in glioblastoma multiforme (GBM). However,
the mechanisms regulating Rictor expression in these tumors is not clearly
understood. In this report, we demonstrate that Rictor is regulated at the level
of mRNA translation via heat-shock transcription factor 1 (HSF1)-induced HuR
activity. HuR is shown to directly bind the 3' untranslated region of the Rictor
transcript and enhance translational efficiency. Moreover, we demonstrate that
mTORC2/AKT signaling activates HSF1 resulting in a feed-forward cascade in which
continued mTORC2 activity is able to drive Rictor expression. RNAi-mediated
blockade of AKT, HSF1 or HuR is sufficient to downregulate Rictor and inhibit GBM
growth and invasive characteristics in vitro and suppress xenograft growth in
mice. Modulation of AKT or HSF1 activity via the ectopic expression of mutant
alleles support the ability of AKT to activate HSF1 and demonstrate continued
HSF1/HuR/Rictor signaling in the context of AKT knockdown. We further show that
constitutive overexpression of HuR is able to maintain Rictor expression under
conditions of AKT or HSF1 loss. The expression of these components is also
examined in patient GBM samples and correlative associations between the relative
expression of these factors support the presence of these signaling relationships
in GBM. These data support a role for a feed-forward loop mechanism by which
mTORC2 activity stimulates Rictor translational efficiency via an AKT/HSF1/HuR
signaling cascade resulting in enhanced mTORC2 activity in these tumors.
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