Lycorine weakens tamoxifen resistance of breast cancer via abrogating HAGLR‐mediated epigenetic suppression on VGLL4 by DNMT1

Much is known about the significance of lycorine, a natural alkaloid, in combating various types of cancer, including breast cancer (BC), but whether it participates in regulating tamoxifen (TAM) resistance and its underlying mechanism remain to be elucidated. Tamoxifen-resistant (TAMR) BC cells were first established by continuously exposed to increasing concentrations of TAM. Levels of targeted gene including HOXD antisense growth-associated lncRNA (HAGLR) and Vestigial like family member 4 (VGLL4) were analyzed by qRT-PCR and western blot, respectively. Cell proliferation ability was assessed by MTT and EdU assays. Flow cytometry was carried out to evaluate the apoptosis. VGLL4 promoter methylation was examined using methylation specific PCR (MSP). The role of HAGLR acting on the expression of VGLL4 via DNA hypermethylation was confirmed by RNA immunoprecipitation (RIP). Here, we reported that lycorine administration reduced the survival ratio of TAMR BC cells, decreased the IC50 of TAM, and strengthened TAM-induced apoptosis. HAGLR, observed to be highly expressed in TAMR BC cells, was identified to be a downstream effector of lycorine, of which overexpression abolished lycorine-mediated TAMR inhibition. VGLL4 served as a target of HAGLR in regulating lycorine-mediated suppression on tamoxifen resistance of TAMR BC cells. Mechanistically, HAGLR epigenetically suppressed VGLL4 expression via DNA methyltransferase 1 (DNMT1)-mediated DNA hypermethylation. Taken together, our data highlights the pivotal role of lycorine in TAM resistance of BC, which may provide a potential agent for improving the effectiveness and efficacy of BC resistance.