ArticleNature medicine2018
Noncanonical hedgehog pathway activation through SRF-MKL1 promotes drug resistance in basal cell carcinomas.
Article in Nature medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed, 112 citations in OpenAlex.
- Identification of the MRTFA/SRF pathway as a critical regulator of quiescence and chemotherapy resistance in cancer.Cancer letters · 2026Article
- Does Basal Cell Carcinoma Arise from a Precursor Lesion?The Journal of investigative dermatology · 2026Review
- One-Pot Gateway to Quinazoline-Thiohydantoin Fused Scaffolds and Discovery of Their Antileukemic Activity.JACS Au · 2026Article
- The immune landscape of melanoma microenvironmental crosstalk.Frontiers in immunology · 2026Review
- Alcian blue-positive stromal phenotype in basal cell carcinoma is associated with progression on first-line hedgehog inhibitors.The journal of pathology. Clinical research · 2026Article
- Exploring the Complexity of Cutaneous Squamous CellCarcinoma Microenvironment: Focus on Immune Cell Roles by Novel 3D In Vitro Models.Life (Basel, Switzerland) · 2025Review
- Enhanced neuromorphogenesis of neural stem cells via the optimization of physical stimulus-responsive signaling pathways.Stem cell research & therapy · 2025Article
- Hedgehog pathway, cell cycle, and primary cilium.Cell death discovery · 2025Review
- The universal role of adaptive transcription in health and disease.The FEBS journal · 2025Review
- Sonic hedgehog signalling pathway in CNS tumours: its role and therapeutic implications.Molecular brain · 2024Review
- A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1 -altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1 - amplified Versus GLI1- rearranged Tumors.The American journal of surgical pathology · 2024Article
- Hedgehog pathway and cancer: A new area (Review).Oncology reports · 2024Review
- Tissue Mechanics and Hedgehog Signaling Crosstalk as a Key Epithelial-Stromal Interplay in Cancer Development.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Biomarkers in Cutaneous Keratinocyte Carcinomas.Dermatology and therapy · 2024Review
- Causal association between skin cancer and immune cells: mendelian randomization (MR) study.BMC cancer · 2024Article
- Imperatorin Suppresses Aberrant Hedgehog Pathway and Overcomes Smoothened Antagonist Resistance via STAT3 Inhibition.Drug design, development and therapy · 2024Article
- Unraveling the landscape of non-melanoma skin cancer through single-cell RNA sequencing technology.Frontiers in oncology · 2024Review
- Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy.MedComm · 2023Review
- MKL/SRF and Bcl6 mutual transcriptional repression safeguards the fate and positioning of neocortical progenitor cells mediated by RhoA.Science advances · 2023Article
- Role of Rho/MRTF in Aggressive Vemurafenib-Resistant Murine Melanomas and Immune Checkpoint Upregulation.International journal of molecular sciences · 2023Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.