Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling

Das, Shamik; Jackson, W. P. U.; Prasain, Jeevan K.; Hanna, Ann; Bailey, Sarah; Tucker, J. Allan; Bae, Sejong; Wilson, Landon; Samant, Rajeev S.; Barnes, Stephen; Shevde, Lalita A.

doi:10.1038/srep40773

Cited by 8 publications

(13 citation statements)

References 48 publications

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“…Since NRF2 promotes Hh signaling, stress-induced NRF2 stabilization might enhance Hh signaling, which might protect cells from damage in some way. Although Hh signaling stimulation by oxidative stress and cytoprotective effects of Hh signaling are both reported in the literature 60–65 , our data showed no enhancement of Hh responsiveness by DMF, as mentioned above (Supplementary Fig. S8c).…”

Section: Discussionsupporting

confidence: 62%

NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling

Martin-Hurtado

Martin-Morales

Robledinos-Antón

et al. 2019

Sci Rep

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The transcription factor NRF2 is a master regulator of cellular antioxidant and detoxification responses, but it also regulates other processes such as autophagy and pluripotency. In human embryonic stem cells (hESCs), NRF2 antagonizes neuroectoderm differentiation, which only occurs after NRF2 is repressed via a Primary Cilia-Autophagy-NRF2 (PAN) axis. However, the functional connections between NRF2 and primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae, remain poorly understood. For instance, nothing is known about whether NRF2 affects cilia, or whether cilia regulation of NRF2 extends beyond hESCs. Here, we show that NRF2 and primary cilia reciprocally regulate each other. First, we demonstrate that fibroblasts lacking primary cilia have higher NRF2 activity, which is rescued by autophagy-activating mTOR inhibitors, indicating that the PAN axis also operates in differentiated cells. Furthermore, NRF2 controls cilia formation and function. NRF2-null cells grow fewer and shorter cilia and display impaired Hedgehog signaling, a cilia-dependent pathway. These defects are not due to increased oxidative stress or ciliophagy, but rather to NRF2 promoting expression of multiple ciliogenic and Hedgehog pathway genes. Among these, we focused on GLI2 and GLI3, the transcription factors controlling Hh pathway output. Both their mRNA and protein levels are reduced in NRF2-null cells, consistent with their gene promoters containing consensus ARE sequences predicted to bind NRF2. Moreover, GLI2 and GLI3 fail to accumulate at the ciliary tip of NRF2-null cells upon Hh pathway activation. Given the importance of NRF2 and ciliary signaling in human disease, our data may have important biomedical implications.

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Section: Discussionsupporting

confidence: 62%

NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling

Martin-Hurtado

Martin-Morales

Robledinos-Antón

et al. 2019

Sci Rep

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“…An interesting possibility is that ciliogenesis and Hh signaling may also contribute to the cytoprotective functions of NRF2. Consistent with this, several reports indicate that redox stress affects primary cilia and Hh signaling, which in turn protect cells against such stress [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

Section: Discussionsupporting

confidence: 70%

“…In many of these diseases, a prominent role is played by redox, proteostatic and other kinds of cellular stress [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Consistently, primary cilia and Hh signaling can respond to redox and other stress signals, and their function may also protect cells from such stresses [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. In this context, recent findings connecting primary cilia and Hh signaling to NRF2 (nuclear factor erythroid 2-related factor 2) are of special relevance.…”

Section: Primary Cilia As Cellular Antennaementioning

confidence: 99%

NRF2 and Primary Cilia: An Emerging Partnership

et al. 2020

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When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.

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“…MCF7 (ATCC, Manassas, VA) and MCF10AT (Karmanos Cancer Center) cell lines were stably knocked down for NF2, generating MCF7 KD and MCF10AT KD, respectively, and cultured as previously described [6,18]. SUM159 cell lines (Asterand Biosciences, Detroit, MI) were stably restored for NF2 by transducing pLV-CMV-NF2-GFP-2A-Puro lentiviral particles (Capital Biosciences, Gaithersburg, MD) and cultured as previously described [6,18]. The cell lines T47D and BT474 knocked out for NF2 were acquired from Synthego, Redwood City, CA and named T47D KD and BT474 KD, respectively.…”

Section: Human Cell Linesmentioning

confidence: 99%

Merlin deficiency alters the redox management program in breast cancer

et al. 2021

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The expression of Merlin tumor suppressor protein encoded by NF2 gene is remarkably decreased in metastatic breast cancer tissues. In order to recapitulate clinical evidence, we generated a unique, conditional Nf2-knockout (Nf2-/-) mouse mammary tumor model. Merlin-deficient breast tumor cells and Nf2-/mouse embryonic fibroblasts (MEFs) displayed a robustly invasive phenotype. Moreover, Nf2-/-MEFs presented with notable alterations in redox management networks, implicating a role for Merlin in redox homeostasis. This programmatic alteration resonated with pathways that emerged from breast tumor cells engineered for Merlin deficiency. Further investigations revealed that NF2silenced cells supported reduced activity of the Nrf2 antioxidant transcription factor, concomitant with elevated expression of NADPH oxidase enzymes. Importantly, mammary specific Nf2-/in an MMTV Neu+ murine breast cancer model demonstrated accelerated mammary carcinogenesis in vivo. Tumor-derived primary organoids and cell lines were characteristically invasive with evidence of a dysregulated cellular redox management system. As such, Merlin deficiency programmatically influences redox imbalance that orchestrates malignant attributes of mammary/breast cancer.

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Loss of Merlin induces metabolomic adaptation that engages dependence on Hedgehog signaling

Cited by 8 publications

References 48 publications

NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling

NRF2-dependent gene expression promotes ciliogenesis and Hedgehog signaling

NRF2 and Primary Cilia: An Emerging Partnership

Merlin deficiency alters the redox management program in breast cancer

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