Department of Hematology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, Henan Province, China.
Department of Hematology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, Henan Province, China.
J Pharmacol Sci. 2022 May;149(1):27-36. doi: 10.1016/j.jphs.2022.01.013. Epub 2022 Feb 17.
Multiple myeloma (MM) is a malignant tumor of plasma cells in the bone marrow. Circular RNAs (circRNAs) exert important activity in the tumorigenesis and chemoresistance of MM. In the current work, we sought to identify the expression, activity, and mechanism of circPSAP activity in MM.
CircPSAP, microRNA (miR)-331-3p, and histone deacetylase 4 (HDAC4) were quantified by qRT-PCR and immunoblotting assays. Cell proliferation and survival were assessed by CCK-8 assay. Cell cycle and apoptosis were detected by flow cytometry. The direct relationship between miR-331-3p and circPSAP or HDAC4 3'UTR was validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays.
CircPSAP was overexpressed in human MM and high levels of circPSAP predicted poor prognosis in MM patients. CircPSAP depletion repressed cell proliferation and promoted apoptosis and BTZ sensitivity. Mechanistically, circPSAP functioned as a miR-331-3p sponge, and circPSAP regulated cell proliferation, apoptosis and BTZ sensitivity by sponging miR-331-3p. MiR-331-3p directly targeted and inhibited HDAC4. MiR-331-3p-mediated inhibition of HDAC4 impaired cell proliferation and enhanced cell apoptosis and BTZ sensitivity. Moreover, circPSAP modulated HDAC4 expression by acting as a miR-331-3p sponge.
Our findings highlight a novel mechanism, in which circPSAP functions as a miR-331-3p sponge to impact MM cell proliferation, apoptosis and BTZ sensitivity by regulating HDAC4 expression.
多发性骨髓瘤（MM）是骨髓中浆细胞的恶性肿瘤。环状 RNA（circRNA）在 MM 的肿瘤发生和化疗耐药中发挥重要作用。在目前的工作中，我们试图确定 circPSAP 在 MM 中的表达、活性和机制。
通过 qRT-PCR 和免疫印迹检测 circPSAP、microRNA（miR）-331-3p 和组蛋白去乙酰化酶 4（HDAC4）的表达。通过 CCK-8 测定评估细胞增殖和存活。通过流式细胞术检测细胞周期和凋亡。通过双荧光素酶报告、RNA 下拉和 RNA 免疫沉淀（RIP）实验验证 miR-331-3p 与 circPSAP 或 HDAC4 3'UTR 的直接关系。
circPSAP 在人 MM 中过度表达，高水平的 circPSAP 预示 MM 患者预后不良。circPSAP 耗竭抑制细胞增殖并促进细胞凋亡和 BTZ 敏感性。机制上，circPSAP 作为 miR-331-3p 的海绵，通过海绵 miR-331-3p 调节细胞增殖、凋亡和 BTZ 敏感性。miR-331-3p 直接靶向并抑制 HDAC4。miR-331-3p 介导的 HDAC4 抑制损害细胞增殖并增强细胞凋亡和 BTZ 敏感性。此外，circPSAP 通过作为 miR-331-3p 海绵调节 HDAC4 表达。
我们的研究结果强调了一种新的机制，即 circPSAP 作为 miR-331-3p 海绵通过调节 HDAC4 表达影响 MM 细胞增殖、凋亡和 BTZ 敏感性。
