KIAA1429 regulates the expression of RAB27B in a m6A YTHDF1 axis-dependent manner and promotes the progression of chronic myeloid leukemia, serving as a potential therapeutic target

Abstract

Abstract Background: Chronic myeloid leukemia (CML) is one of the most common adult leukemias. The considerable negative changes in its acute phase and the adverse drug effects could lead to poor prognosis. N6-methyladenine (m6A) modification plays an important regulatory role in physiological and pathological processes. KIAA1429 is an important m6A regulator, but the biological role of KIAA1429 in CML is still unclear. Methods: RT-qPCR and Western blot were used to analyze the differential expression of KIAA1429 in CML clinical samples and cell lines. CCK-8, EdU staining, flow cytometry, Transwellassay, cellular morphology evaluation, and liquid chromatography-mass spectrometry (LC-MS) were further implemented to assess the changes in the biological functions of CML cell lines with KIAA1429 knockdown or overexpression. In addition, subcutaneous tumorigenesis experiment in nude mice was performed for in vivo function assessment. The combination of MeRIP-seq and mRNA-seq predicted that RAB27B is a downstream target gene of KIAA1429. RIP-qPCR, RNA stability analysis, SELECT, and “rescue” experiments were then conducted to explore the mechanisms underlying the regulation of KIAA1429/m6A/YTHDF1 axis on RAB27B. Finally, the inhibitory effects of rucaparib on KIAA1429 and CML were explored in vitro and in vivo. Results: The m6A and KIAA1429 expression was significantly upregulated in patients with blast phase CML. KIAA1429 was found to regulate the total level of RNA m6A modification in the CML cells and to promote the malignant biological behaviors of CML cells, including proliferation, migration, and imatinib resistance. Inhibiting KIAA1429 in CML cells regulated the stability of RAB27B mRNA through the m6A/YTHDF1 axis, consequently inhibiting CML proliferation and drug efflux, and ultimately increasing cell sensitivity to imatinib. Rucaparib suppressed the expression of KIAA1429 and CML cell proliferation, and promoted cell apoptosis. The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib. Rucaparib inhibited the tumorigenesis capability of CML cells in vivo. Conclusions: Elevated KIAA1429 expression in the blast phase of CML enhanced the stability of RAB27B mRNA through the m6A/YTHDF1 axis to upregulate RAB27B expression, and thus promoting CML progression. Therefore, rucaparib exerts inhibitory effects on KIAA1429 expression and CML progression.