Purpose: MORC4 has recently been characterized as a breast cancer-associated anti-apoptotic oncoprotein. In the current study, we explored its downstream regulation in luminal A/B breast tumors.
Materials and Methods: Bioinformatic prediction was performed using data from The Cancer Genome Atlas (TCGA)-breast cancer (BRCA). Cellular and molecular studies were conducted using luminal A/B representative MCF-7 and BT-474 cell lines.
Results: ENST00000355610.8 (encoding MORC4a isoform) was the dominant transcript in breast cancer. ChIP-qPCR and dual-luciferase assay confirmed two STAT3-binding sites in the MID2  promoter in both MCF-7 and BT-474 cells. Co-IP confirmed an interaction between MORC4 and STAT3. ChIP-qPCR data indicated that MORC4  inhibition led to remarkably decreased enrichment of the STAT3-binding MID2  promoter segments. MORC4  overexpression significantly elevated BCL-2 expression in MCF-7 cells and increased their resistance to adriamycin (ADM), 5-fluorouracil (5-FU), and cisplatin (DDP). MID2  inhibition largely abrogated MORC4-induced drug-resistance. However, the drug-resistant phenotype was rescued by overexpressing MID2-MT that was resistant to MID2  siRNA.
Conclusion: This study revealed a novel regulatory mechanism of MORC4 on MID2  expression via STAT3-mediated transcriptional activation. This regulatory axis might confer increased chemoresistance to breast cancer cells.
Keywords: MORC4, STAT3, MID2, chemoresistance, luminal A/B breast cancer