Fig. 9
Correlative expression of LINC00115, methylated-PLK3, and SETDB1 are prognostic. A Representative images of SETDB1, PLK3-K106me1, PLK3-K200me1, HIF1α, and LINC00115 in 118 clinical TNBC metastatic lymph node tissues. Scale bars, 50 μm. B Correlation of expression levels between SETDB1, PLK3K-106me1, PLK3K-200me1, HIF1α, and LINC00115. C Prognosis comparison of breast cancer patients with SETDB1/PLK3-K106me1 or -K200me1 ectopic differential expression using Kaplan-Meier survival analysis. D A working model of LINC00115 regulating chemoresistance breast cancer cell stemness and metastasis through SETDB1/PLK3/HIF1α signaling. PTX therapy upregulates LINC00115 in BCSCs. LINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3 and enhance SETDB1 methylation of PLK3 at both K106 and K200. PLK3 methylation reduces phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in decreased degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes, contributing to chemoresistance and metastasis. Targeting SETDB1 with a small molecular inhibitor reduces LINC00115-mediated BCSCs stemness and HIF1α expression and enhances BCSCs response to PTX.