Effect of knockdown PHF8 on the transcriptional regulation of BCR-ABL1 fusion gene on CML cell line K562
Epigenetic dysregulation plays a vital role in the pathogenesis of hematological malignancies. Histone demethylation is a key mechanism for epigenetic modification, of which dysregulation has an immeasurable effect on both TKI resistance and the transformation from CP CML to AP/BC CML. Here we report that PHF8 regulate the transcription of the driven fusion gene BCR-ABL1 in CML cells. The depletion of PHF8 promotes differentiation and inhibits proliferation. Furthermore, the proliferation-inhibited function of PHF8-knockdown have stronger effect on imatinib mesylate (IM)-resistant CML cells. We identified that PHF8 as a transcriptional modulator interacted with the promoter of the BCR::ABL1 fusion gene and alters the methylation levels of H3K9me1, H3K9me2 and H3K27me1, thereby promoting BCR::ABL1 transcription. Taken together, PHF8, as an oncogenic protein, was abnormally expressed in CML, altered the histone methylation levels of BCR::ABL1 promoter, and upregulated BCR::ABL1. Our study indicated that regulating histone demethylation is essential for BCR::ABL1 expression. Targeting PHF8 can be a promising therapeutic option for CML patients with TKI resistance. Overall design: To investigate the mechanism and function of PHF8 in CML, we constructed the PHF8 knockdown CML cell lines with shRNA in K562. Than we performed gene expression profiling analysis using data obtained from RNA-seq of K562 with shNC and shPHF8.