Enhancer RNA from STAT3 locus affects temozolomide chemoresistance of glioblastoma cells

Less than ten percent of glioblastoma tumors are sensitive to temozolomide, the primary drug for treating this type of cancer. STAT3 is a well-known regulator of glioblastoma resistance to temozolomide, suppression of its activity sensitizes cells to the treatment. However, systemic suppression of STAT3 may lead to immune dysregulation, possibly interfering with the antitumor effect. Non-coding RNAs expressed from enhancers (enhancer RNA or eRNA) can guide the direction of various cellular processes by controlling the expression of key genes. In this work, we found eRNA from the STAT3 locus (TMZR1-eRNA) that controls the sensitivity of glioblastoma cells to temozolomide. Knockdown of TMZR1-eRNA decreased STAT3 mRNA and protein expression, resulting in a profound reduction in the abundance of temozolomide-treated cells. Using the reporter assay, we showed that eRNA suppression reduced the activity of STAT3 promoter. Patient glioblastoma cells with higher eRNA expression also showed enhanced sensitivity to temozolomide upon eRNA knockdown. Expression of the eRNA in healthy brain tissue and PBMC was observed at markedly lower levels. Taken together, our results suggest TMZR1-eRNA suppression as a more targeted approach to STAT3 inhibition, potentially with minimal side effects.