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Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC. The invasion of epithelial tumours often depends on the epithelial-mesenchymal transition. Here, the authors report that intracellular activation of thyroid hormone by the D2 deiodinase enzyme promotes invasion and progression of squamous cell carcinoma by transcriptionally up-regulating ZEB-1.

Background:Thyroid Hormones (THs) critically impact human cancer. Although endowed with both tumor-promoting and inhibiting effects in different cancer types, excess of THs has been linked to enhanced tumor growth and progression. Breast cancer depends on the interaction between bulk tumor cells and the surrounding microenvironment in which mesenchymal stem cells (MSCs) exert powerful pro-tumorigenic activities.Methods:Primary human MSCs from healthy female donors were co-cultured with DIO2 knock out (D2KO) and wild type (WT) MCF7 breast cancer cells to assess cell growth, migration, invasion and the expression of known epithelial-mesenchymal transition (EMT)- and inflammation-related markers. Furthermore, a surgery-free intraductal delivery model, i.e., the Mouse-INtraDuctal (MIND) injection method, was used as a tool for in vivo characterization of breast tumor formation and progression.Results:In this study, we uncovered a novel role of THs in regulating the tumor-stroma crosstalk. MCF7 cells enhanced the intracellular activation of THs through the TH-activating enzyme, D2, fostering their EMT properties and the dialogue with MSCs. D2 inactivation reduced the invasiveness of MCF7 cells and their responsiveness to the pro-tumorigenic induction via MSCs, both in vivo and in vitro.Conclusions:Thus, we argue that intracellular activation of THs via D2 is a critical requirement for invasive and metastatic conversion of breast cancer cells, advising the blocking of D2 as a potential therapeutic tool for cancer therapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

There are significant commonalities among several pathologies involving fibroblasts, ranging from auto-immune diseases to fibrosis and cancer. Early steps in cancer development and progression are closely linked to fibroblast senescence and transformation into tumor-promoting cancer-associated fibroblasts (CAFs), suppressed by the androgen receptor (AR). Here, we identify ANKRD1 as a mesenchymal-specific transcriptional coregulator under direct AR negative control in human dermal fibroblasts (HDFs) and a key driver of CAF conversion, independent of cellular senescence. ANKRD1 expression in CAFs is associated with poor survival in HNSCC, lung, and cervical SCC patients, and controls a specific gene expression program of myofibroblast CAFs (my-CAFs). ANKRD1 binds to the regulatory region of my-CAF effector genes in concert with AP-1 transcription factors, and promotes c-JUN and FOS association. Targeting ANKRD1 disrupts AP-1 complex formation, reverses CAF activation, and blocks the pro-tumorigenic properties of CAFs in an orthotopic skin cancer model. ANKRD1 thus represents a target for fibroblast-directed therapy in cancer and potentially beyond. The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.

Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology.

The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms. Thyroid hormones have an important role in fostering tumour progression, however their upstream regulators are less clear. Here, the authors identify the thyroid hormone activating enzyme type 2 deiodinase as a p53 target gene and demonstrate its contribution to tumour progression in p53 mutant squamous cell carcinoma.

Epigenetic mechanisms oversee epidermal homeostasis and oncogenesis. The identification of kinases controlling these processes has direct therapeutic implications. We show that ULK3 is a nuclear kinase with elevated expression levels in squamous cell carcinomas (SCCs) arising in multiple body sites, including skin and Head/Neck. ULK3 loss by gene silencing or deletion reduces proliferation and clonogenicity of human keratinocytes and SCC-derived cells and affects transcription impinging on stem cell-related and metabolism programs. Mechanistically, ULK3 directly binds and regulates the activity of two histone arginine methyltransferases, PRMT1 and PRMT5 (PRMT1/5), with ULK3 loss compromising PRMT1/5 chromatin association to specific genes and overall methylation of histone H4, a shared target of these enzymes. These findings are of translational significance, as downmodulating ULK3 by RNA interference or locked antisense nucleic acids (LNAs) blunts the proliferation and tumorigenic potential of SCC cells and promotes differentiation in two orthotopic models of skin cancer. The identification of kinases that control epigenetic mechanisms in squamous cell carcinomas (SCCs) can be of therapeutic relevance. Here the authors show that loss of nuclear kinase ULK3 impairs the recruitment of two histone arginine methyltransferases, PRMT1 and PRMT5 to the promoter regions of genes of functions, hence, suppressing the tumorigenic potential of SCC cells.

Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells.

Obesity exacerbates the risk and aggressiveness of many types of cancer. Adipose tissue (AT) represents a prevalent component of the tumor microenvironment (TME) and contributes to cancer development and progression. Reciprocal communication between cancer and adipose cells leads to the generation of cancer‐associated adipocytes (CAAs), which in turn foster tumor invasiveness by producing paracrine metabolites, adipocytokines, and growth factors. Interfering with the crosstalk between CAAs and cancer cells is of key relevance in the prevention of tumor progression. The present study aimed to analyze the contribution of peritumoral AT in renal cell carcinoma (RCC) progression in lean versus overweight or obese patients. By isolating human adipose‐derived stromal/stem cells from the three groups of patients and performing conditioned medium studies with RCC cells along with in vivo xenograft experiments, we found that peritumoral adipocytes from the three groups show a distinct expression profile of genes. In particular, ADAM metallopeptidase domain 12 (ADAM12) and cytochrome P450 family 1 subfamily B member 1 (CYP1B1) were found to be upregulated in obesity and their silencing reduced RCC cell invasiveness. In conclusion, high ADAM12 and CYP1B1 expressions in the peritumoral adipocytes boost tumor invasiveness and may serve as an indicator of poor prognosis in RCC. Tumor microenvironment drives cancer formation and progression. We analyzed the role of human cancer‐associated adipocytes from patients with renal cell carcinoma (RCC) stratified as lean, overweight, or obese. RNA‐seq demonstrated that, among the most altered genes involved in the tumor–stroma crosstalk, are ADAM12 and CYP1B1, which were proven to be key promoters of RCC tumorigenesis. These findings add insight into fat‐driven cancerogenesis.

The thyroid hormone-inactivating (TH-inactivating) enzyme type 3 iodothyronine deiodinase (D3) is an oncofetal protein that is rarely expressed in adult life but has been shown to be reactivated in the context of proliferation and neoplasms. D3 terminates TH action within the tumor microenvironment, thereby enhancing cancer cell proliferation. However, the pathological role of D3 and the contribution of TH metabolism in cancer have yet to be fully explored. Here, we describe a reciprocal regulation between TH action and the cancer-associated microRNA-21 (miR21) in basal cell carcinoma (BCC) skin tumors. We found that, besides being negatively regulated by TH at the transcriptional level, miR21 attenuates the TH signal by increasing D3 levels. The ability of miR21 to positively regulate D3 was mediated by the tumor suppressor gene GRHL3, a hitherto unrecognized D3 transcriptional inhibitor. Finally, in a BCC mouse model, keratinocyte-specific D3 depletion markedly reduced tumor growth. Together, our results establish TH action as a critical hub of multiple oncogenic pathways and provide functional and mechanistic evidence of the involvement of TH metabolism in BCC tumorigenesis. Moreover, our results identify a miR21/GRHL3/D3 axis that reduces TH in the tumor microenvironment and has potential to be targeted as a therapeutic approach to BCC.