ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma.
Rohit SachdevaMegan WuSandra SmiljanicOleksandra KaskunKimia Ghannad-ZadehAngela CelebreKeren IsaevA Sorana MorrissyJennifer GuanJiefei TongJeffrey ChanTaylor M WilsonSayf Al-OmaishiDavid G MunozPeter B DirksMichael F MoranMichael D TaylorJüri ReimandSunit DasPublished in: Cancer research (2019)
Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. SIGNIFICANCE: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
Keyphrases
- transcription factor
- induced apoptosis
- dna binding
- cell cycle arrest
- free survival
- gene expression
- papillary thyroid
- poor prognosis
- locally advanced
- endoplasmic reticulum stress
- small cell lung cancer
- cell death
- squamous cell carcinoma
- oxidative stress
- newly diagnosed
- cell proliferation
- epidermal growth factor receptor
- cell therapy
- machine learning
- tyrosine kinase
- emergency department
- stem cells
- heat shock
- deep learning
- dna methylation
- binding protein
- smoking cessation
- radiation therapy
- protein protein
- young adults
- artificial intelligence