Abstract
The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells. By comparison, LSD1 inhibitors as single agents exhibit little cytotoxicity against RMS cells. Mechanistically, GSK690 acts in concert with JNJ-26481585 to upregulate mRNA levels of the proapoptotic BH3-only proteins BMF, PUMA, BIM and NOXA. This increase in mRNA levels is accompanied by a corresponding upregulation of BMF, PUMA, BIM and NOXA protein levels. Importantly, individual knockdown of either BMF, BIM or NOXA significantly reduces GSK690/JNJ-26481585-mediated cell death. Similarly, genetic silencing of BAK significantly rescues cell death upon GSK690/JNJ-26481585 cotreatment. Also, overexpression of antiapoptotic BCL-2 or MCL-1 significantly protects RMS cells from GSK690/JNJ-26481585-induced cell death. Furthermore, GSK690 acts in concert with JNJ-26481585 to increase activation of caspase-9 and -3. Consistently, addition of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly reduces GSK690/JNJ-26481585-mediated cell death. In conclusion, concomitant LSD1 and HDAC inhibition synergistically induces cell death in RMS cells by shifting the ratio of pro- and antiapoptotic BCL-2 proteins in favor of apoptosis, thereby engaging the intrinsic apoptotic pathway. This indicates that combined treatment with LSD1 and HDAC inhibitors is a promising new therapeutic approach in RMS.
Highlights
RMS represents the most frequent soft-tissue sarcoma in children and comprises two major subtypes, that is, embryonal RMS and alveolar RMS.[1,2,3] Despite multimodal therapy consisting of surgery, chemotherapy and radiation, the overall survival for patients with advanced disease is still very poor.[4]
We show that GSK690 and JNJ-26481585 act together to induce intrinsic apoptosis by changing the ratio of pro- and antiapoptotic BCL-2 proteins in favor of apoptosis
The overall shift towards proapoptotic BH3-only proteins is likely to be critical for the synergistic induction of cell death, as the portfolio of individual BH3-only proteins that is increased by GSK690/JNJ-26481585 cotreatment varies between the investigated cell lines
Summary
RMS represents the most frequent soft-tissue sarcoma in children and comprises two major subtypes, that is, embryonal RMS (eRMS) and alveolar RMS (aRMS).[1,2,3] Despite multimodal therapy consisting of surgery, chemotherapy and radiation, the overall survival for patients with advanced disease is still very poor.[4]. More specific LSD1 inhibitors have been developed, some of which have already progressed to clinical trials for the treatment of leukemia or lung cancer.[27,28] High LSD1 levels have been detected in several types of solid tumors or hematological malignancies and have been associated with poor prognosis.[19] Recently, LSD1 has been shown to be overexpressed in primary RMS samples.[29,30] little is yet known about whether or not LSD1 may serve as a therapeutic target in RMS. The current study aims at investigating the potential of LSD1 inhibition in RMS cells, either alone or in combination with other epigenetic modifiers such as HDAC inhibitors
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