The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer

Res Sq. 2023 Sep 8:rs.3.rs-3266720. doi: 10.21203/rs.3.rs-3266720/v1. Preprint.ABSTRACTThe alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER + breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1 , KLF4 , YAP1 , SNAI1 , and MYC . Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML -depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous l...
Source: Cell Research - Category: Cytology Authors: Source Type: research