Histone deacetylase inhibitor prevents cell growth in Burkitt’s lymphoma by regulating PI3K/Akt pathways and leads to upregulation of miR-143, miR-145, and miR-101

Abstract

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma more common in children comprising one third of pediatric non-Hodgkin lymphoma cases. The recent discovery in BL pathogenesis highlighted the activation of PI3K pathway in cooperation with Myc in the development of BL. In this study, we demonstrated that PI3K/Akt pathway is a target to histone deacetylase inhibitor (HDACi) in BL cells. The combination of HDACi (sodium butyrate, NaB) and chemotherapy (VP-16) inhibited 51 % of the proliferation and enhanced the blockage of the cell cycle progression at G2/M with a concurrent decrease in the S phase. Microarray profiling showed a synergistic action of NaB/VP-16 combination through the differential regulation of 1,413 genes. Comparing VP-16 treatment with the NaB/VP-16 combination, 318 genes were deregulated: 250 genes were downregulated, and 68 were upregulated when compared with untreated cells. Among these genes, six (CDKN1A, CCND1, FAS, CHEK2, MDM4, and SESN2) belong to the p53-signaling pathway. The activation of this signaling pathway is usually induced by stress signals and ultimately leads to cell cycle arrest. Besides, the inhibition of the cell growth was related to reduced Akt phosphorylation, and decrease of c-Myc protein expression by about 60 % (p ≤ 0.005). Moreover, HDACi enhanced miR-101, miR-143, and miR-145 levels in BL cell line, which were inversely associated with the levels of miR-101, miR-143, and miR-145 found to be extremely downregulated in the sample of BL patients. We highlight the fact that effective combinations of HDACis with other target drugs could improve BL therapy in the future.

MicroRNA-145 inhibits the activation of the mTOR signaling pathway to suppress the proliferation and invasion of invasive pituitary adenoma cells by targeting AKT3 in vivo and in vitro

“…Based on the results, miR-145 played an inhibitor role of PI3K and AKT3 in IPA. miR-145, as one of the suppressor mRNAs, has been found to be downregulated in many cancer cells 28. Decreased expression of miR-145 is observed both in vivo and in vitro, which is important for the development and progression of prostate cancer 29.…”

miR-143-3p inhibits the proliferation, migration and invasion in osteosarcoma by targeting FOSL2

“…The down-regulation of miR-143 expression has also been reported in several human cancers, including colorectal cancer 23 , prostate cancer 26 , cervical cancer 27 , ovarian cancer 28 and B-cell lymphoma 29 . Thus, it is considered that miR-143 is a tumor-suppressor miRNA.…”

Mir 145/143: tumor suppressor, oncogenic microenvironmental factor or ...both?

“…For example, we have shown that the mir-143/145 promoter is actively hyper-methylated in mesothelioma cancer cell lines4 and that hyper-methylation of this promoter correlates with the progressive downregulation of the mir-143/145 in brain metastases of lung tumors, as opposed to primary lung tumors and, lastly, to normal lung tissue [ 7 ]. Furthermore, treatment with histone deacetylase inhibitors and de-methylating agents or ectopic restoration of the miRNA levels correlates with lack of tumorigenicity in vivo [ 7 ] and similar results were shown in Burkitt's lymphoma cells [ 8 ]. The tumor specimens used in the mentioned studies were composed for a large portion of tumor tissue (typically 85-90% of the total tissue) and represented the results of the analysis from many different institutions.…”