LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

Novel NCOA2/3-rearranged low-grade fibroblastic spindle cell tumors: A report of five cases.

Spindle cell mesenchymal neoplasms are a diverse and often challenging diagnostic group. While morphological impression is sufficient for some diagnoses, increasingly immunohistochemical and even molecular data is required to render an accurate diagnosis, which can lead to the characterization of new entities. We describe five cases of novel mesenchymal neoplasms with rearrangements in the NCOA2 and NCOA3 genes partnered with either CTCF or CRTC1. Three tumors occurred in the head and neck (palate, auditory canal), while the other two were in visceral organs (lung, urinary bladder). All cases occurred in adults (range 33-86) with a median age of 42 and fairly even sex distribution = (male-to-female = 3:2). Morphologically, they had similar features consisting of monotonous, bland spindle to ovoid cells with fascicular and reticular arrangements in a myxohyaline to collagenous stroma. However, immunophenotypically they had essentially a null phenotype, with only two tumors staining partially for CD34 and smooth muscle actin. Targeted RNA sequencing detected in-frame CTCF::NCOA2 (one case), CRTC1::NCOA2 (two cases), and CTCF::NCOA3 (two cases) fusions. Treatment was surgical resection in all cases. Local recurrence and/or distant metastases were not observed in any case (median follow-up, 7.5 months; range, 2-19 months). Given their morphologic, immunohistochemical, and molecular similarities, we believe that these cases may represent an emerging family of low-grade NCOA2/3-rearranged fibroblastic spindle cell neoplasms.

Novel CRTC1::MRTFB(MKL2) Gene Fusion Detected in Myxoid Mesenchymal Neoplasms With Myogenic Differentiation Involving Bone and Soft Tissues.

Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.

Undifferentiated Round Cell Sarcoma With CRTC1::SS18 Fusion: Expanding Clinicopathologic Features of a Rare Translocation Sarcoma With Prominent Desmoplastic Stroma.

Undifferentiated round cell sarcomas (URCS) represent a diverse group of tumors, including conventional Ewing sarcoma, round cell sarcoma with EWSR1/FUS-non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR alterations. Since 2018, 3 cases of URCS with a novel CRTC1::SS18 gene fusion have been reported in the literature. Herein, we report 3 additional cases of CRTC1::SS18 sarcoma, thereby doubling the number of described cases and expanding the clinicopathologic features of this rare translocation sarcoma. Together with the previously reported cases, we show that the male-to-female ratio is 1:2 with a median age of 34 years (range, 12-42 years). Tumors occurred primarily in intramuscular locations involving the lower extremity. Histologically, all tumors contained uniform round-to-epithelioid cells with a moderate amount of eosinophilic cytoplasm growing in sheets and nests with prominent desmoplastic stroma reminiscent of desmoplastic small round cell tumor. Immunohistochemical results were nonspecific, demonstrating variable expression of CD99 (patchy), ALK, GATA3, and cyclin D1. RNA sequencing revealed CRTC1::SS18 gene fusions in all cases, involving exons 1 to 2 of CRTC1 (the 5' partner gene) on chromosome 19 and either exon 2 or exon 4 of SS18 (the 3' partner gene) on chromosome 18. The clinical course was variable. Although 1 previously reported case demonstrated aggressive behavior with a fatal outcome, 2 others had a relatively indolent course with gradual growth for 6 to 7 years prior to resection. Two cases developed metastatic disease, including 1 case with bilateral lung metastasis and 1 with locoregional spread to a lymph node. By analyzing the clinicopathologic features, we aimed to improve recognition of this rare translocation sarcoma to better understand its biologic potential, optimize patient management, and expand the current classification of URCS.

D-arabinose acts as antidepressant by activating the ACSS2-PPARγ/TFEB axis and CRTC1 transcription.

CREB-regulated transcription coactivator 1 (CRTC1), a pivotal synaptonuclear messenger, regulates synaptic plasticity and transmission to prevent depression. Despite exhaustive investigations into CRTC1 mRNA reductions in the depressed mice, the regulatory mechanisms governing its transcription remain elusive. Consequently, exploring rapid but non-toxic CRTC1 inducers at the transcriptional level is important for resisting depression. Here, we demonstrate the potential of D-arabinose, a unique monosaccharide prevalent in edible-medicinal plants, to rapidly enter the brain and induce CRTC1 expression, thereby eliciting rapid-acting and persistent antidepressant responses in chronic restrain stress (CRS)-induced depressed mice. Mechanistically, D-arabinose induces the expressions of peroxisome proliferator-activated receptor gamma (PPARγ) and transcription factor EB (TFEB), thereby activating CRTC1 transcription. Notably, we elucidate the pivotal role of the acetyl-CoA synthetase short-chain family member 2 (ACSS2) as an obligatory mediator for PPARγ and TFEB to potentiate CRTC1 transcription. Furthermore, D-arabinose augments ACSS2-dependent CRTC1 transcription by activating AMPK through lysosomal AXIN-LKB1 pathway. Correspondingly, the hippocampal down-regulations of ACSS2, PPARγ or TFEB alone failed to reverse CRTC1 reductions in CRS-exposure mice, ultimately abolishing the anti-depressant efficacy of D-arabinose. In summary, our study unveils a previously unexplored role of D-arabinose in activating the ACSS2-PPARγ/TFEB-CRTC1 axis, presenting it as a promising avenue for the prevention and treatment of depression.

Molecular characterization, spatio-temporal expression patterns of crtc2 gene and its immune roles in yellow catfish (Pelteobagrus fulvidraco).

cAMP response element binding (CREB) protein 2 (CRTC2) is a transcriptional coactivator of CREB and plays an important role in the immune system. Thus far, the physiological roles of Crtc2 in teleost are still poorly understood. In this study, the crtc2 gene was identified and characterized from yellow catfish (Pelteobagrus fulvidraco; therefore, the gene is termed as pfcrtc2), and its evolutionary and molecular characteristics as well as potential immunity-related roles were investigated. Our results showed that the open reading frame of pfcrtc2 was 2346 bp in length, encoding a protein with 781 amino acids. Gene structure analysis revealed its existence of 14 exons and 13 introns. A phylogenetic analysis proved that the tree of crtc2 was clustered into five groups, exhibiting a similar evolutionary topology with species evolution. Multiple protein sequences alignment demonstrated high conservation of the crtc2 in various vertebrates with similar structure. Syntenic and gene structural comparisons further established that crtc2 was highly conserved, implying its similar roles in diverse vertebrates. Tissue distribution pattern detected by quantitative real-time PCR showed that the pfcrtc2 gene was almost expressed in all detected tissues except for eyes, with the highest expression levels in the gonad, indicating that Crtc2 may play important roles in various tissues. In addition, pfcrtc2 was transcribed at all developmental stages in yellow catfish, showing the highest expression levels at 12 h after fertilization. Finally, the transcriptional profiles of crtc2 were significantly increased in yellow catfishes injected with Aeromonas hydrophila or Poly I:C, which shared a consistent change pattern with four immune-related genes including IL-17A, IL-10, MAPKp38, and NF-κBp65, suggesting pfCrtc2 may play critical roles in preventing both exogenous bacteria and virus invasion. In summary, our findings lay a solid foundation for further studies on the functions of pfcrtc2, and provide novel genetic loci for developing new strategies to control disease outbreak in teleost.

Ulcerated CRTC1::TRIM11 cutaneous tumor with metastases.

CRTC1::TRIM11 cutaneous tumor (CTCT) is a rare skin tumor of uncertain differentiation. In the 49 reported cases, only four cases showed regional or distant metastasis, but follow-up remains limited. Herein, we present a case of metastatic CTCT with ulceration, a histological feature that has not been previously described. A 75-year-old male with a 2-month history of toe ulceration underwent a shave biopsy, which showed a dermal nodular neoplasm that was immunoreactive for SOX10 and S100, negative for Melan-A, and was initially diagnosed as melanoma. Upon pathology review at our institution, the tumor was composed of intersecting fascicles and nests of epithelioid and spindle cells. Additional immunohistochemistry revealed immunoreactivity of the tumor for MiTF and NTRK and negativity for HMB-45 and PRAME. Next-generation sequencing identified CRTC1::TRIM11 fusion, leading to a revised diagnosis of CTCT. The patient proceeded to a toe amputation and sentinel lymph node (SLN) biopsy 5 months after the shave biopsy. The amputation showed residual CTCT and a focus on lymphovascular invasion. The SLN revealed multifocal subcapsular metastases. The patient was started on adjuvant nivolumab and showed biopsy-proven recurrence in the right inguinal lymph nodes and imaging findings suspicious for pulmonary metastases 8 months after the excision. In summary, we present a case of CTCT with ulceration and lymphovascular invasion. We also provide additional evidence that a subset of CTCT behaves aggressively. The optimal surgical and medical treatments are unknown.

Crtc modulates fasting programs associated with 1-C metabolism and inhibition of insulin signaling.

Fasting in mammals promotes increases in circulating glucagon and decreases in circulating insulin that stimulate catabolic programs and facilitate a transition from glucose to lipid burning. The second messenger cAMP mediates effects of glucagon on fasting metabolism, in part by promoting the phosphorylation of CREB and the dephosphorylation of the cAMP-regulated transcriptional coactivators (CRTCs) in hepatocytes. In Drosophila, fasting also triggers activation of the single Crtc homolog in neurons, via the PKA-mediated phosphorylation and inhibition of salt-inducible kinases. Crtc mutant flies are more sensitive to starvation and oxidative stress, although the underlying mechanism remains unclear. Here we use RNA sequencing to identify Crtc target genes that are up-regulated in response to starvation. We found that Crtc stimulates a subset of fasting-inducible genes that have conserved CREB binding sites. In keeping with its role in the starvation response, Crtc was found to induce the expression of genes that inhibit insulin secretion (Lst) and insulin signaling (Impl2). In parallel, Crtc also promoted the expression of genes involved in one-carbon (1-C) metabolism. Within the 1-C pathway, Crtc stimulated the expression of enzymes that encode modulators of S-adenosyl-methionine metabolism (Gnmt and Sardh) and purine synthesis (ade2 and AdSl) Collectively, our results point to an important role for the CREB/CRTC pathway in promoting energy balance in the context of nutrient stress.

Genetic and Immunohistochemical Profiling of Mammary Hidradenoma and Comparison to Mucoepidermoid Carcinoma.

Mucoepidermoid carcinoma (MEC) is exceedingly rare in the breast, with <45 cases reported in the literature. Although estrogen receptor/progesterone receptor/human epidermal growth factor 2 triple-negative, MEC is characterized as a special subtype of breast carcinoma with significantly better prognosis than conventional basal-type tumors. Cutaneous hidradenoma (HA) is considered a benign adnexal neoplasm showing histomorphologic overlap with MEC. Rare cases of HA have also been reported in the breast, but these are relatively uncharacterized. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and genetic features of 8 breast HAs, in comparison to 3 mammary MECs. All cases were positive for MAML2 break-apart fluorescence in situ hybridization. Eight cases demonstrated a CRTC1::MAML2 fusion, and one MEC harbored a CRTC3::MAML2 fusion; the latter is a novel finding in the breast. Mutational burden was very low, with only one HA exhibiting a MAP3K1 pathogenic alteration. By IHC, both MEC and HA demonstrated cell type-dependent expression of high- and low-molecular-weight keratins and p63, as well as negative to low-positive estrogen receptor and androgen receptor. Smooth muscle myosin and calponin highlighted an in situ component in the 3 cases of MEC; expression of these myoepithelial markers was negative in HAs. Additional distinguishing characteristics included the growth pattern and tumor architecture, the presence of glandular/luminal cells in HA, and overall higher IHC expression of SOX10, S100 protein, MUC4, and mammaglobin in MEC. Morphologic findings were also compared to a series of 27 cutaneous nonmammary HAs. Mucinous and glandular/luminal cells were identified in significantly more mammary HAs than nonmammary lesions. The findings provide insight into the pathogenesis of MAML2-rearranged neoplasms of the breast, underscore the overlapping genetic features of MEC and HA, and highlight similarities to their extramammary counterparts.

Microglia sense and suppress epileptic neuronal hyperexcitability.

Microglia are the resident immune cells of the central nervous system, undertaking surveillance role and reacting to brain homeostasis and neurological diseases. Recent studies indicate that microglia modulate epilepsy-induced neuronal activities, however, the mechanisms underlying microglia-neuron communication in epilepsy are still unclear. Here we report that epileptic neuronal hyperexcitability activates microglia and drives microglial ATP/ADP hydrolyzing ectoenzyme CD39 (encoded by Entpd1) expression via recruiting the cAMP responsive element binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) from cytoplasm to the nucleus and binding to CREB. Activated microglia in turn suppress epileptic neuronal hyperexcitability in a CD39 dependent manner. Disrupting microglial CREB/CRTC1 signaling, however, decreases CD39 expression and diminishes the inhibitory effect of microglia on epileptic neuronal hyperexcitability. Overall, our findings reveal CD39-dependent control of epileptic neuronal hyperexcitability by microglia is through an excitation-transcription coupling mechanism.

Primary mucoepidermoid carcinoma of the external auditory canal with a CRTC1::MAML2 fusion: A case report and a review of literature.

Mucoepidermoid carcinoma is a malignant neoplasm of exocrine glands that arises predominantly in salivary glands. It is seldom encountered as a primary cutaneous neoplasm, and in those patients, it often involves the external auditory canal. Given their rarity, they can pose a diagnostic challenge and prompt extensive workup. In salivary glands, mucoepidermoid carcinomas commonly harbor CRTC1/3::MAML2 fusions; however, genetic alterations of primary cutaneous neoplasms are less characterized, with previous studies reporting CRTC1 rearrangements in the absence of MAML2 aberrations. Herein, we report a case of a primary cutaneous mucoepidermoid carcinoma of the external auditory canal with a CRTC1::MAML2 rearrangement. We also review the clinical, morphologic, and molecular features of this neoplasm and compare them to those reported in the literature and to histopathologic mimics.

One step at a time: Melanocytic differentiation in fusion-driven cutaneous neoplasms.

As dermatopathologists, we routinely diagnose melanocytic nevi, melanomas, and occasionally melanocytomas in our daily clinical practice. However, it is now clearly established that the presence of melanocytic differentiation in a tumor does not necessarily indicate any of the aforementioned diagnoses. Tumors such as clear cell sarcoma, malignant melanotic nerve sheath tumor, PEComa, melanotic neuroectodermic tumor of infancy, and even certain translocation-associated renal cell carcinomas all share the common characteristic of melanin synthesis. Over the past two decades, with the advent of molecular diagnostics, there has been an explosion of new data and discoveries in this field. Examples such as CRTC1::TRIM11 cutaneous tumors and MITF pathway-activated melanocytic tumors (ACTIN::MITF and MITF::CREM) have been incorporated into the latest edition of the WHO classification of skin tumors (5th ed). In a recent issue, Alexandrescu et al. reported another case of a dermal/subcutaneous melanocytic tumor harboring a MITF::CREM1 translocation. In a separate paper within the current issue, Li et al. present a case of clear cell sarcoma with the rare EWSR1::CREM fusion, which had initially been misdiagnosed as melanoma with regional and distant metastases. We warmly welcome these two very interesting and high-quality articles to our journal, and we eagerly anticipate what the future holds for this fascinating category of tumors.

Nicotine pretreatment alleviates MK-801-induced behavioral and cognitive deficits in mice by regulating Pdlim5/CRTC1 in the PFC.

Increasing evidence shows that smoking-obtained nicotine is indicated to improve cognition and mitigate certain symptoms of schizophrenia. In this study, we investigated whether chronic nicotine treatment alleviated MK-801-induced schizophrenia-like symptoms and cognitive impairment in mice. Mice were injected with MK-801 (0.2 mg/kg, i.p.), and the behavioral deficits were assessed using prepulse inhibition (PPI) and T-maze tests. We showed that MK-801 caused cognitive impairment accompanied by increased expression of PDZ and LIM domain 5 (Pdlim5), an adaptor protein that is critically associated with schizophrenia, in the prefrontal cortex (PFC). Pretreatment with nicotine (0.2 mg · kg-1 · d-1, s.c., for 2 weeks) significantly ameliorated MK-801-induced schizophrenia-like symptoms and cognitive impairment by reversing the increased Pdlim5 expression levels in the PFC. In addition, pretreatment with nicotine prevented the MK-801-induced decrease in CREB-regulated transcription coactivator 1 (CRTC1), a coactivator of CREB that plays an important role in cognition. Furthermore, MK-801 neither induced schizophrenia-like behaviors nor decreased CRTC1 levels in the PFC of Pdlim5-/- mice. Overexpression of Pdlim5 in the PFC through intra-PFC infusion of an adreno-associated virus AAV-Pdlim5 induced significant schizophrenia-like symptoms and cognitive impairment. In conclusion, chronic nicotine treatment alleviates schizophrenia-induced memory deficits in mice by regulating Pdlim5 and CRTC1 expression in the PFC.

Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts.

Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.

Salivary mucoepidermoid carcinoma: histological variants, grading systems, CRTC1/3-MAML2 fusions, and clinicopathological features.

AIMS: To investigate the histological diversity of salivary mucoepidermoid carcinoma (MEC), its clinicopathological features, and its associations with CRTC1/3-MAML2 fusions. METHODS AND RESULTS: Salivary MEC cases (n = 177) were examined for CRTC1/3-MAML2 fusions, histological variants were classified, and tumours were graded according to four different grading systems. Adverse histological features considered to be unusual in MEC were also investigated. Of the 177 MEC cases, 110 were positive for CRTC1/3-MAML2 fusions. The classical variant was the most frequent in the fusion-positive case group, the fusion-negative case group, and the total case group. The clear/oncocytic variant was the second most frequent in the fusion-positive and total case groups. Oncocytic, Warthin-like and spindle variants were seen in the fusion-positive case group only. Clear cell, sclerosing, mucinous and central variants were seen in both the fusion-positive case group and the fusion-negative case group. No case was classified as a ciliated variant, as a mucoacinar variant, or as a high-grade transformation. As compared with the classical variant, non-classical variants were characterised by frequent CRTC1/3-MAML2 fusions and a low clinical stage in all cases. Of the four histological features considered to be unusual in MEC, marked nuclear atypia, frequent mitoses (>10/10 high-power fields) and extensive necrosis were found independently of the fusion status, and were present in 3-5% of all cases. However, none of the cases showed overt keratinisation. On comparison, the Armed Forces Institute of Pathology and modified Healey grading systems downgraded tumours, the Brandwein system upgraded tumours, and the Memorial Sloan Kettering system provided a moderate means of assessment. CONCLUSION: Recognition of the histological diversity of MEC, its clinicopathological features and its associations with CRTC1/3-MAML2 fusions is helpful for an accurate diagnosis of this carcinoma.

Activation of Crtc2/Creb1 in skeletal muscle enhances weight loss during intermittent fasting.

The Creb-Regulated Transcriptional Coactivator (Crtc) family of transcriptional coregulators drive Creb1-mediated transcription effects on metabolism in many tissues, but the in vivo effects of Crtc2/Creb1 transcription on skeletal muscle metabolism are not known. Skeletal muscle-specific overexpression of Crtc2 (Crtc2 mice) induced greater mitochondrial activity, metabolic flux capacity for both carbohydrates and fats, improved glucose tolerance and insulin sensitivity, and increased oxidative capacity, supported by upregulation of key metabolic genes. Crtc2 overexpression led to greater weight loss during alternate day fasting (ADF), selective loss of fat rather than lean mass, maintenance of higher energy expenditure during the fast and reduced binge-eating during the feeding period. ADF downregulated most of the mitochondrial electron transport genes, and other regulators of mitochondrial function, that were substantially reversed by Crtc2-driven transcription. Glucocorticoids acted with AMPK to drive atrophy and mitophagy, which was reversed by Crtc2/Creb1 signaling. Crtc2/Creb1-mediated signaling coordinates metabolic adaptations in skeletal muscle that explain how Crtc2/Creb1 regulates metabolism and weight loss.

Endoplasmic reticulum stress downregulates PGC-1α in skeletal muscle through ATF4 and an mTOR-mediated reduction of CRTC2.

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. METHODS: The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. RESULTS: Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. CONCLUSIONS: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. Video Abstract.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion and prominent epidermal involvement: A case report.

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMCT) is a recently described entity with only 13 cases reported in the literature. Histopathologically, the neoplasm consists of atypical epithelioid to spindled cells that form a well-circumscribed nodule usually confined to the dermis and subcutis with cytological features including large vesicular nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemistry shows variable expressivity of melanocytic markers. Currently, there are limited data regarding long-term outcomes of this newly described entity. Most cases have done well, but there is one case reported with an adverse event. Hence, further studies are needed to accurately classify this tumor. Definitive diagnosis is made by laboratory evidence of CMCT. Herein, we report the first case of CMCT with epidermal involvement in the youngest patient known to be affected to date.

Non-sebaceous lymphadenoma-like mucoepidermoid carcinoma: A case report.

Non-sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non-sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3-MAML2 fusion gene are well-known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non-sebaceous lymphadenoma and CRTC1-MAML2 fusion gene. The patient was an 83-year-old woman with an 8-year history of a solid, well-circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular-cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non-sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non-sebaceous lymphadenoma-like mucoepidermoid carcinoma was made based on the presence of the CRTC1-MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.