Epithelial-mesenchymal transition (EMT) in carcinoma cells enhances malignant progression by promoting invasion and survival. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and by the E-box-binding transcription factors Twist, Snail and ZEB. Grainyhead-like-2 (GRHL2), a member of the mammalian Grainyhead family of wound healing regulatory transcription factors, suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. In this study, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter, in the case of Six1, through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel and suppressed the emergence of CD44highCD24low cells (defining the cancer stem cell phenotype in the cell type studied). GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this phenotypic transition, modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression by direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. Together, our observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression.
The mammalian homologs of the D. melanogaster Grainyhead gene, Grainyhead-like 1-3 (GRHL1, GRHL2 and GRHL3), are transcription factors implicated in wound healing, tubulogenesis and cancer. Their induced target genes encode diverse epithelial cell adhesion molecules, while mesenchymal genes involved in cell migration and invasion are repressed. Moreover, GRHL2 suppresses the oncogenic epithelial-mesencyhmal transition, thereby acting as a tumor suppressor. Mechanisms, some involving established cancer-related signaling/transcription factor pathways (for example, Wnt, TGF-β, mir200, ZEB1, OVOL2, p63 and p300) and translational implications of the Grainyhead proteins in cancer are discussed in this review article.
Resistance to anoikis is a pre-requisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by re-sensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity were investigated. EMT enhanced mitochondrial oxidative metabolism. While this was accompanied by higher accumulation of superoxide, the overall level of Reactive Oxygen Species (ROS) declined, due to decreased hydrogen peroxide. Glutamate Dehydrogenase 1 (GLUD1) expression increased in EMT, and this increase, via the product α-ketoglutarate (α-KG), was important for suppressing hydrogen peroxide and protecting against anoikis. GRHL2 suppressed GLUD1 gene expression, decreased α-KG, increased ROS and sensitized cells to anoikis. Implications These results demonstrate a mechanistic role for GRHL2 in promoting anoikis through metabolic alterations.
GRHL2 suppresses EMT to give a default epithelial phenotype. GRHL2 inhibits this process through the histone acetyltransferase coactivator p300, repressing the partial EMT and preventing induction of MMPs. The results demonstrate novel roles for p300 and GRHL2 in promoting or suppressing EMT in morphogenesis and tumor progression.
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.
ImportanceAssessment of response after radiotherapy (RT) using 18F–fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT) is routine in managing head and neck squamous cell carcinoma (HNSCC). Freeform reporting may contribute to a clinician’s misunderstanding of the nuclear medicine (NM) physician’s image interpretation, with important clinical implications.ObjectiveTo assess clinician-perceived freeform report meaning and discordance with NM interpretation using the modified Deauville score (MDS).Design, Setting, and ParticipantsIn this retrospective cohort study that was conducted at an academic referral center and National Cancer Institute–designated Comprehensive Cancer Center and included patients with HNSCC treated with RT between January 2014 and December 2019 with a posttreatment PET/CT and 1 year or longer of follow-up, 4 masked clinicians independently reviewed freeform PET/CT reports and assigned perceived MDS responses. Interrater reliability was determined. Clinician consensus–perceived MDS was then compared with the criterion standard NM MDS response derived from image review. Data analysis was conducted between December 2021 and February 2022.ExposuresPatients were treated with RT in either the definitive or adjuvant setting, with or without concurrent chemotherapy. They then underwent posttreatment PET/CT response assessment.Main Outcomes and MeasuresClinician-perceived (based on the freeform PET/CT report) and NM-defined response categories were assigned according to MDS. Clinical outcomes included locoregional control, progression-free survival, and overall survival.ResultsA total of 171 patients were included (45 women [26.3%]; median [IQR] age, 61 [54-65] years), with 149 (87%) with stage III to IV disease. Of these patients, 52 (30%) received postoperative RT and 153 (89%) received concurrent chemotherapy. Interrater reliability was moderate (κ = 0.68) among oncology clinicians and minimal (κ = 0.36) between clinician consensus and NM. Exact agreement between clinician consensus and the NM was 64%. The NM-rated MDS was significantly associated with locoregional control, progression-free survival, and overall survival.Conclusions and RelevanceThe results of this cohort study suggest that considerable variation in perceived meaning exists among oncology clinicians reading freeform HNSCC post-RT PET/CT reports, with only minimal agreement between MDS derived from clinician perception and NM image interpretation. The NM use of a standardized reporting system, such as MDS, may improve clinician-NM communication and increase the value of HNSCC post-RT PET/CT reports.
Background To describe intensity‐modulated radiotherapy (IMRT) with Gamma Knife Radiosurgery (GKRS) boost for locally advanced head and neck cancer (HNC) with disease near dose‐limiting structures. Methods Patients with HNC treated with IMRT/GKRS as part of a combined modality approach between 2011 and 2021 were reviewed. Local control, overall survival and disease‐specific survival were estimated using the Kaplan Meier method. Results Twenty patients were included. Nineteen patients had T3‐4 tumors. Median follow‐up was 26.3 months. GKRS site control was 95%. Two patients progressed at the treated primary site, one patient failed at the edge of the GKRS treatment volume, with no perineural or intracranial failure. 2‐year OS was 94.7% (95% CI: 85.2%–100%). Concurrent chemotherapy was given in nine patients (45%). One patient (5%) received induction/concurrent chemotherapy. Brain radionecrosis occurred in three patients, one of which was biopsy‐proven. Conclusions IMRT plus GKRS boost results in excellent disease control near critical structures with minimal toxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.