The landscape of GPCR in the skin epidermal stem cells: From the basic to the clinical.

Skin, as the body's largest organ, acts as the primary defense mechanism against infection and injury. The maintenance of skin health heavily relies on the regulation of epidermal stem cells, crucial for ensuring epidermal homeostasis, hair regeneration, and the repair of epidermal injuries. Recent studies have placed a growing emphasis on G protein-coupled receptor (GPCR) in the context of understanding epidermal stem cells, uncovering its significant role in determining their fate.

Melanocortin 1 receptor mediates melanin production by interacting with the BBSome in primary cilia.

Production of melanin pigments is a protective mechanism of the skin against ultraviolet (UV)-induced damage and carcinogenesis. However, the molecular basis for melanogenesis is still poorly understood. Herein, we demonstrate a critical interplay between the primary cilium and the melanocortin 1 receptor (MC1R) signaling.

Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation.

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response.

Astragaloside IV enhances the sensitivity of breast cancer stem cells to paclitaxel by inhibiting stemness.

Background: Chemotherapy is one of the common treatments for breast cancer. The induction of cancer stem cells (CSCs) is an important reason for chemotherapy failure and breast cancer recurrence. Astragaloside IV (ASIV) is one of the effective components of the traditional Chinese medicine (TCM) , which can improve the sensitivity of various tumors to chemotherapy drugs.

Stem cell heterogeneity, plasticity, and regulation.

As a population of homogeneous cells with both self-renewal and differentiation potential, stem cell pools are highly compartmentalized and contain distinct subsets that exhibit stable but limited heterogeneity during homeostasis. However, their striking plasticity is showcased under natural or artificial stress, such as injury, transplantation, cancer, and aging, leading to changes in their phenotype, constitution, metabolism, and function. The complex and diverse network of cell-extrinsic niches and signaling pathways, together with cell-intrinsic genetic and epigenetic regulators, tightly regulate both the heterogeneity during homeostasis and the plasticity under perturbation.

Melanogenesis and the Targeted Therapy of Melanoma.

Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma.

Genome-wide CRISPR/Cas9 library screen identifies PCMT1 as a critical driver of ovarian cancer metastasis.

Background: The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance.

The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes.

Variants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype.

Melanosome transport and regulation in development and disease.

Melanosomes are specialized membrane-bound organelles that synthesize and organize melanin, ultimately providing color to the skin, hair, and eyes. Disorders in melanogenesis and melanosome transport are linked to pigmentary diseases, such as Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, and Griscelli syndrome. Clinical cases of these pigmentary diseases shed light on the molecular mechanisms that control melanosome-related pathways.

Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads.

Some genetic melanocortin-1 receptor (MC1R) variants responsible for human red hair color (RHC-variants) are consequently associated with increased melanoma risk. Although MC1R signaling is critically dependent on its palmitoylation primarily mediated by the ZDHHC13 protein-acyl transferase, whether increasing MC1R palmitoylation represents a viable therapeutic target to limit melanomagenesis in redheads is unknown. Here we identify a specific and efficient in vivo strategy to induce MC1R palmitoylation for therapeutic benefit.

Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis.

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation.

Targeting the upstream transcriptional activator of PD-L1 as an alternative strategy in melanoma therapy.

Programmed cell death ligand 1 (PD-L1) interacts with programmed cell death protein-1 (PD-1) as an immune checkpoint. Reactivating the immune response by inhibiting PD-L1 using therapeutic antibodies provides substantial clinical benefits in many, though not all, melanoma patients. However, transcriptional suppression of PD-L1 expression as an alternative therapeutic anti-melanoma strategy has not been exploited.

AMP-activated protein kinase protects against necroptosis via regulation of Keap1-PGAM5 complex.

Background: The AMP-activated protein kinase (AMPK) plays critical roles in growth regulation and metabolism reprogramming. AMPK activation protects cells against apoptosis from injury in different cell and animal models. However, its function in necroptosis remains largely unclear.

The protective role of DOT1L in UV-induced melanomagenesis.

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma.

The molecular classification of astrocytic tumors.

Aim: This study will explore the genetic and epigenetic alterations in astrocytomas, and identify the critical molecular signatures and signaling pathways for prognosis assessment by multiplatform comprehensive analysis.

Method: We performed integration analyses of incorporating DNA methylation, mRNA expression, microRNA expression, and long non-coding RNA (lncRNA) expression in 33 astrocytic tumor tissues and 9 non-tumor brain tissues.

Result: We observed that 11,795 DNA methylation sites, 3,627 genes, 136 microRNAs, and 3,334 lncRNAs were significantly differential between tumors and non-tumor brain tissues, and the filtered signatures through comprehensive analysis were significantly enriched in calcium signaling pathway.

Palmitoylation-dependent activation of MC1R prevents melanomagenesis.

The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma.

The APC/C E3 Ligase Complex Activator FZR1 Restricts BRAF Oncogenic Function.

BRAF drives tumorigenesis by coordinating the activation of the RAS/RAF/MEK/ERK oncogenic signaling cascade. However, upstream pathways governing BRAF kinase activity and protein stability remain undefined. Here, we report that in primary cells with active APC, APC earmarks BRAF for ubiquitination-mediated proteolysis, whereas in cancer cells with APC-free FZR1, FZR1 suppresses BRAF through disrupting BRAF dimerization.

LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors.

Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown.

O-linked GlcNAcylation elevated by HPV E6 mediates viral oncogenesis.

High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered.

Germline MC1R status influences somatic mutation burden in melanoma.

The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15-76%) higher than that among persons without an R allele.

Association of Serum Uric Acid Levels in Psoriasis: A Systematic Review and Meta-Analysis.

High levels of serum uric acid (SUAC) are frequently detected in patients with psoriasis. However, the relationship between psoriasis and hyperuricemia remains unknown. Here we conducted a meta-analysis to identify the SUAC levels in subjects with psoriasis and to determine whether there is an associated risk between psoriasis and hyperuricemia.

The E3 ligase APC/C(Cdh1) promotes ubiquitylation-mediated proteolysis of PAX3 to suppress melanocyte proliferation and melanoma growth.

The anaphase-promoting complex or cyclosome with the subunit Cdh1 (APC/C(Cdh1)) is an E3 ubiquitin ligase involved in the control of the cell cycle. Here, we identified sporadic mutations occurring in the genes encoding APC components, including Cdh1, in human melanoma samples and found that loss of APC/C(Cdh1) may promote melanoma development and progression, but not by affecting cell cycle regulatory targets of APC/C. Most of the mutations we found in CDH1 were those associated with ultraviolet light (UV)-induced melanomagenesis.