gdc-0449 and Carcinogenesis

Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.

Topics: Anilides; Animals; Aspirin; Carcinogenesis; Cell Proliferation; Colitis; Colorectal Neoplasms; Disease Models, Animal; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hedgehog Proteins; Humans; Inflammation; Jumonji Domain-Containing Histone Demethylases; Mice; Pyridines; Signal Transduction

Topics: Anilides; Antineoplastic Agents; Basal Cell Nevus Syndrome; Carcinogenesis; Carcinoma, Basal Cell; Cell Line, Tumor; Cilia; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Hedgehog Proteins; Humans; Mutation; Pyridines; ras Proteins; Signal Transduction; Skin Neoplasms

Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC

Topics: Anilides; Animals; Antineoplastic Agents; Carcinogenesis; Female; Hair Follicle; Hedgehog Proteins; Humans; Male; Mice; Pyridines; Rats; Rats, Sprague-Dawley; Signal Transduction; Skin Neoplasms

Topics: Anilides; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinogenesis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Drug Design; Drug Evaluation, Preclinical; Hedgehog Proteins; Humans; Inhibitory Concentration 50; Male; Mice; Molecular Docking Simulation; Nanoparticles; Neoplastic Stem Cells; Organ Specificity; Pancreatic Neoplasms; Pyridines; Smoothened Receptor; Spheroids, Cellular; Structure-Activity Relationship

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Topics: Anilides; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Disease Progression; DNA Mutational Analysis; Exome; Genetic Association Studies; Genetic Predisposition to Disease; HEK293 Cells; Humans; Mutation; Pyridines; Signal Transduction; Skin Neoplasms; Transcriptome