Harmine inhibits ovarian cancer migration and invasion and epithelial-mesenchymal transition (EMT) by inhibiting HDAC7 to restore RECK expression

Harmine, a β-carboline alkaloid derived from Peganum harmala L., exhibits potent Anticancer properties, including the suppression of ovarian Cancer (OC) cell proliferation and metastasis. However, the underlying molecular mechanisms remain incompletely understood. This study demonstrates that harmine significantly inhibits OC cell migration, invasion, and epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Transcriptome Sequencing revealed that harmine downregulates histone deacetylase 7 (HDAC7) while upregulating the reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a tumor suppressor gene frequently silenced in cancers. Functional assays showed that harmine treatment dose- and time-dependently reduced OC cell viability, migration, and invasion, concomitant with elevated RECK expression and suppression of Matrix Metalloproteinases (MMP2, MMP9) and mesenchymal markers (N-Cadherin, Snail, Vimentin), alongside increased E-cadherin levels. Knockdown of RECK abolished these antitumor effects, confirming its pivotal role in harmine-mediated metastasis inhibition. Mechanistically, harmine suppressed HDAC7 expression, and conversely, HDAC7 overexpression reversed harmine's anti-metastatic effects by repressing RECK. Further analysis revealed that HDAC7 binds to transcription factor SP1. Chromatin immunoprecipitation (ChIP) assays confirmed that harmine disrupts this interaction, liberating SP1 to bind the RECK promoter and activate its transcription. Collectively, these findings elucidate a novel HDAC7/RECK/SP1 axis through which harmine exerts its anti-metastatic effects in OC, highlighting its potential as a therapeutic agent for OC treatment.

Harmine; Histone deacetylase 7; Metastasis; Ovarian cancer; Reversion-inducing cysteine-rich protein with Kazal motifs.