Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway

Abstract

Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies.

LINC81507 act as a competing endogenous RNA of miR-199b-5p to facilitate NSCLC proliferation and metastasis via regulating the CAV1/STAT3 pathway

“…LINC00339 sponges miR-145 and interferes FOXM1 to facilitate NSCLC tumorigenesis 16 . MALAT1 activates Akt/mTOR signaling via targeting miR-206 to accelerate NSCLC cells migration and invasion 17 .…”

<p>Metformin Combined with 4SC-202 Inhibited the Migration and Invasion of OSCC via STAT3/TWIST1</p>

“… 12 , 45 , 46 HDACi also exerts its tumor inhibitory impact through STAT3, as the class II HDAC inhibitor mercaptoacetamide suppresses migration and invasion in human glioma cells by inhibiting FAK/STAT3, 47 and class I HDAC inhibitor chidamide and BG45 inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling. 48 , 49 Thus, STAT3 could be the target of anticancer drugs. Our results revealed that phosphorylation of STAT3 decreased under metformin or/and 4SC-202 treatment, suggesting metformin or/and 4SC-202 may suppress TWIST1 through STAT3, and intriguingly, combination of metformin and 4SC-202 had a more dramatic inhibition that either alone.…”

Sirt1 gene confers Adriamycin resistance in DLBCL via activating the PCG-1α mitochondrial metabolic pathway

“…Thereafter, the cells were harvested, washed with phosphate buffered saline (PBS), and stained using an Annexin V-FITC/PI apoptosis kit (BD Biosciences, San Jose, CA, USA) by following the manufacturer's instructions. The cells were measured using FCM and Cell Quest software (BD Biosciences) [40].…”

“…Western blotting analysis was performed to analyze protein expression. The primary antibodies (Sirt1, PGC1-α, Caspase3, PARP, TFAM, COXI and HO-1) used for western blotting analysis were obtained from Santa Cruz Biotechnology (Inc, CA, USA) or Abcam China Co., Ltd (Shanghai, China) [40,41]. The secondary antibody for western blotting analysis was obtained from Cell signaling Technology (Beverly, MA, USA) or Abcam China Co., Ltd (Shanghai, China).…”