Recently, hydrogen sulphide (H2S) has been acknowledged as a pivotal gasotransmitter altering several oncogenic signaling pathways in breast cancer (BC). Our research group has recently identified H2S and its synthesizing enzyme cystathionine-γ-lyase (CSE) as promising targets for BC treatment especially that their expression pattern was closely associated with aggressive tumor phenotypes. However, the motor engines responsible for such high expression pattern of CSE/H2S in BC patients are yet to be explored. Transcriptomic analysis for CSE promoter region has revealed STAT-3 as a direct regulator for CSE. Long non-coding RNAs (lncRNAs) have recently been identified as vital post-transcriptional regulators. Yet, lncRNAs regulating H2S production is still a virgin field. MALAT-1 is an oncogenic lncRNA tuning self-renewal capacity of BC cells. However, the role of MALAT-1 in modulating STAT-3-regulated CSE has never been probed in BC. Therefore, our aim is to investigate the role of MALAT-1 in regulating STAT-3/CSE/H2S axis.
BC biopsies and their normal counterparts were collected from 20 BC patients. MDA-MB-231 cells were cultured and transiently transfected using MALAT-1 and CSE siRNAs by lipofection method. Total RNA was extracted using Biozol reagent, reverse transcribed and quantified using qRT-PCR. Western blot analysis was performed.
Screening showed an upregulation of MALAT-1, STAT-3 and CSE in aggressive BC tissues. Upon knocking down of MALAT-1, a marked repression of STAT-3 and CSE was observed nominating MALAT-1 as a novel upstream lncRNA regulating STAT-3/CSE axis. On the other hand, CSE siRNAs resulted in the induction of MALAT-1 expression level, STAT-3 transcript and phosphorylated forms in attempt to restore H2S levels in BC cells.
MALAT-1 was identified as the first lncRNA regulating STAT-3/CSE/ H2S in BC. Furthermore, this study underscores the significance of dual targeting of MALAT-1 and CSE for efficient repression of H2S levels in BC cells by-passing the compensatory mechanism exercised by CSE.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.