HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications
T Harada1, H Ohguchi1, Y Grondin2
1Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Abstract:
Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clinical efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clinical activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degradation of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), respectively, triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
Insights
Targeting histone deacetylase 3 (HDAC3) and DNA methyltransferase 1 (DNMT1) simultaneously shows promise for treating multiple myeloma (MM). This combination therapy downregulates cancer cell proliferation and induces apoptosis, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Histone deacetylases (HDACs) are therapeutic targets in cancer, including multiple myeloma (MM).
- Non-selective HDAC inhibitors have shown efficacy but cause side effects.
- Selective HDAC inhibition may offer improved therapeutic outcomes.
Purpose of the Study:
- To investigate the role of HDAC3 in MM cell proliferation.
- To evaluate the efficacy of combined HDAC3 and DNA methyltransferase 1 (DNMT1) inhibition in MM.
Main Methods:
- Genetic knockdown of HDAC3, HDAC1, and HDAC2.
- Treatment with selective HDAC3 inhibitor (BG45) and DNMT1 inhibitor (5-azacytidine, AZA).
- Assessment of DNMT1 expression, c-Myc degradation, DNMT1 stability, cell proliferation, apoptosis, and in vivo efficacy in a murine xenograft model.
Main Results:
- HDAC3 inhibition, but not HDAC1 or HDAC2, downregulates DNMT1 expression and inhibits MM cell proliferation.
- HDAC3 inhibition leads to c-Myc degradation and DNMT1 hyperacetylation, reducing DNMT1 stability.
- Combined BG45 and AZA treatment synergistically inhibits MM cell growth and induces apoptosis in vitro and in vivo.
Conclusions:
- HDAC3 inhibition plays a critical role in regulating DNMT1 expression and MM cell proliferation.
- Combination therapy with an HDAC3 inhibitor and a DNMT1 inhibitor demonstrates significant anti-MM activity.
- This combination strategy warrants further investigation for improving MM patient outcomes.
