Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway

Abstract

Irregular histone modification and aberrant lncRNAs expression are closely related to the occurrence of tumors including acute myeloid leukemia (AML). However, the effects and specific underlying molecular mechanism of histone deacetylase inhibitors on lncRNA expression in AML cells are unclear. Here, we reported the effects of a novel histone deacetylase inhibitor Chidamide on proliferation and lncRNA expression in AML cells. Chidamide inhibited cell proliferation, blocked G1/S phase transition, and induced cell apoptosis through the caspase-dependent apoptotic pathway in AML cells. Chidamide also inhibited the formation of subcutaneous tumors. Transcriptome sequencing results showed that 1,195 lncRNAs were co-upregulated and 780 lncRNAs were codownregulated after Chidamide treatment of SKM-1 cells and THP-1 cells. Combined with transcriptome sequencing data and the gene expression profiling interactive analysis dataset, we found that VPS9D1-AS1 expression was negatively correlated with the survival of AML patients. VPS9D1-AS1 knockdown inhibited cell proliferation, arrested cell cycle, as well as inhibited the formation of subcutaneous tumors in vivo. VPS9D1-AS1 overexpression had the reverse effect. Furthermore, VPS9D1-AS1 knockdown inhibited the MEK/ERK signaling pathway, and thus enhanced the inhibitory effect of Chidamide on AML cell proliferation. These findings suggested that targeted regulation of VPS9D1-AS1 might overcome the limitations of Chidamide in the treatment of AML.

Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma

“…Since chidamide inhibited cell proliferation and induced apoptosis in t-FL cells, we further investigated whether chidamide regulates cell cycle progression, which is one of the main mechanisms by which HDACi induce tumor cell death. In this context, previous studies have shown that G1 arrest appears to be a common response to chidamide in various tumor cells (36)(37)(38). Thus, cell cycle regulators, including cyclins and CDK inhibitors (e.g., p21 and p27), may be tightly controlled by chidamide (27,36,39).…”

Screening a novel signature and predicting the immune landscape of metastatic osteosarcoma in children via immune-related lncRNAs

“…Ferguson et al showed that AL020997.3 enhanced the interleukin 6 expressions for monocytes (27). Several studies have investigated the role of VPS9D1-AS1 in multiple cancer types, such as colorectal cancer, prostate cancer, lung adenocarcinoma, hepatocellular carcinoma, acute myeloid leukemia, acute lymphoblastic leukemia, and gastric cancer (28)(29)(30)(31)(32)(33)(34). Our results showed that metastatic patients had significantly higher lncRNA-VPS9D1-AS1 than localized patients, and the overexpression of lncRNA-VPS9D1-AS1 indicated a poor outcome.…”

HDAC Inhibitor and BCL2 Selective Inhibitor Synergistically Exert Cytotoxicity on Human Myeloma Cells by Upregulating BIM Expression

“…HDACis (such as chidamide) were reported to be effective in killing of a variety of tumor cells, especially in hematological malignancies, including MM through inhibiting cell proliferation and inducing cell cycle arrest, DNA damage, autophagy, ferroptosis, and apoptosis. [12][13][14][15][16][17] It has been reported [18][19][20] that HDACi (including chidamide) could lead to the dysregulation of anti-and pro-apoptotic BCL2 family proteins, such as upregulating pro-apoptotic proteins (e.g., BAX and BAK) and BH3-only proteins (e.g., BIM, BID and PUMA) and decreasing the levels of pro-survival proteins (e.g., BCL2, BCL-X L and MCL1). Previous study has proved that ventoclax can release BIM from pro-survival proteins and thus promotes BIM to dimer with BAX and BAK, which can induce endogenous apoptosis 21 .…”