Deficiency of tumor suppressor Merlin facilitates metabolic adaptation by co-operative engagement of SMAD-Hippo signaling in breast cancer

Abstract

The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-β pathway. This was reflected as dysregulated activation of TGF-β signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD). As a consequence, the loss of Merlin in breast cancer resulted in a significant metabolic and bioenergetic adaptation of cells characterized by increased aerobic glycolysis and decreased oxygen consumption. Mechanistically, we determined that the co-operative activity of the Hippo and TGF-β transcription effectors caused upregulation of the long non-coding RNA Urothelial Cancer-Associated 1 (UCA1) that disengaged Merlin's check on STAT3 activity. The consequent upregulation of Hexokinase 2 (HK2) enabled a metabolic shift towards aerobic glycolysis. In fact, Merlin deficiency engendered cellular dependence on this metabolic adaptation, endorsing a critical role for Merlin in regulating cellular metabolism. This is the first report of Merlin functioning as a molecular restraint on cellular metabolism. Thus, breast cancer patients whose tumors demonstrate concordant loss of Merlin and SMAD7 may benefit from an approach of incorporating STAT3 inhibitors.

Merlin deficiency alters the redox management program in breast cancer

“…Interestingly, they reported that YAP/TAZ function to limit mitochondrial respiration, prevent ROS buildup, and reduce oxidative stress cell death under nutrient stress such as glutamine deprivation [51]. We previously demonstrated that Merlin‐deficient breast cancer cells metabolically adapt toward aerobic glycolysis by co‐operatively engaging SMAD‐Hippo signaling [52]. Our current findings indicate that Merlin deficiency enables ROS accumulation—a contrast to the previous study that can be explained by several factors—our studies are centered on breast cancer cells that do not harbor mutations in NF2 and are not conducted in nutrient‐limiting conditions.…”

miR-193b regulates tumorigenesis in liposarcoma cells via PDGFR, TGFβ, and Wnt signaling

“…PDGFR is known to activate FAK to promote migration 37 , and signaling downstream of both kinases converges on MEK/ERK to support proliferation 38 . Similarly, cooperation of Hippo (YAP1) and TGFβ (SMADs) signaling has been found to promote carcinogenesis 39,40 . Not only does YAP1 regulate Wnt signaling, SMAD4 also controls proteasomal degradation of β-catenin 41 .…”

Current perspectives on inhibitory SMAD7 in health and disease

“…In human skin dermal fibroblasts, YAP/TAZ have been found to inhibit TGF-b signaling by promoting SMAD7 expression via transcription factor AP-1 (Qin et al 2018). Moreover, loss of tumor suppressor Merlin, an upstream activator of the Hippo signaling pathway, leads to unrestrained YAP/TAZ activity and is concordant with decrease of SMAD7 expression (Mota et al 2018).…”