Characterizing a Regulatory Axis in CML Cell Apoptosis
Posted: Monday, March 16, 2020
A new study published in the Journal of Experimental & Clinical Cancer Research provides evidence that deregulation of the signal transducer and activator of transcription 5A (STAT 5A)/microRNA 202-5p (miR-202-5p)/ubiquitin-specific peptidase 15 (USP15)/caspase 6 regulatory axis may suppress chronic myeloid leukemia (CML) cell apoptosis. According to Jian-Min Luo, MD, PhD, of the Second Hospital of Hebei Medical University, China, and colleagues, “targeting this pathway might be a promising therapeutic approach for the treatment of CML.”
The researchers determined the expression levels of USP15, caspase-6, STAT5A-regulated miR-202-5P using polymerase chain reaction and Western blotting in both CML cell lines and peripheral blood mononuclear cells from patients with CML. A combination of flow cytometry, gain and loss-of-function experiments, and xenograft animal models were used to fully characterize the roles and relationship between USP15, miR-202-5p, and STAT5A.
The expression level of USP15 was found to be significantly decreased in both the CML cell lines and in the mononuclear cells. This depletion increased the resistance of cells to imatinib treatment, whereas overexpression of USP15 reduced resistance to imatinib. Decreased ubiquitination activity of USP15 led to a reduction in the caspase-6 level, which attenuated apoptosis in the cancer cells. MicroRNA 202-5p was additionally upregulated in the cancer cell line and had a negative correlation to USP15 expression through direct targeting of the USP15 3´ untranslated region. Therefore, upregulation of miR-202-5p enhanced resistance of CML cells to imatinib by inhibiting apoptosis. STAT5A was upregulated as well in these cells and was found to directly activate miR-202-5p transcription by binding to the pre–miR-202 promoter. Blockade of this STAT5A/miR-202-5p/USP15/caspase-6 regulatory axis via pimozide treatment induced apoptosis and reduced xenograft growth in vivo.
Disclosure: The authors reported no conflicts of interest.