PML modulates epigenetic composition of chromatin to regulate expression of pro-metastatic genes in triple-negative breast cancer

Abstract

The promyelocytic leukemia (PML) protein organizes nuclear aggregates known as PML nuclear bodies (PML-NBs), where many transcription factors localize to be regulated. In addition, associations of PML and PML-NBs with chromatin are described in various cell types, further implicating PML in transcriptional regulation. However, a complete understanding of the functional consequences of PML association to DNA in cellular contexts where it promotes relevant phenotypes is still lacking. We examined PML chromatin association in triple-negative breast cancer (TNBC) cell lines, where it exerts important oncogenic functions. We find that PML associates discontinuously with large heterochromatic PML-associated domains (PADs) that contain discrete gene-rich euchromatic sub-domains locally depleted of PML. PML promotes heterochromatic organization in PADs and expression of pro-metastatic genes embedded in these sub-domains. Importantly, this occurs outside PML-NBs, suggesting that nucleoplasmic PML exerts a relevant gene regulatory function. We also find that PML plays indirect regulatory roles in TNBC cells by promoting the expression of pro-metastatic genes outside PADs. Our findings suggest that PML is an important transcriptional regulator of pro-oncogenic metagenes in TNBC cells, via transcriptional regulation and epigenetic organization of heterochromatin domains that embed regions of local transcriptional activity.

PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma

“…PML was reported to regulate all of these processes, albeit in different cellular systems and sometimes with opposite outcomes. For example, PML inhibits cholesterol biosynthetic pathways also in prostate cancer (Chen et al, 2018 ), but in apparent contrast with our observations PML promotes the expression of extracellular matrix (ECM) remodeling factors in TNBC (Fracassi et al, 2023 ), stimulates inflammation/interferon signaling in different cell types (Hsu and Kao, 2018 ), and induces p53-dependent senescence upon oncogenic insults (Hsu and Kao, 2018 ). Nevertheless, the upregulation of p53-dependent and senescence gene networks (Fig.…”

PML Nuclear bodies: the cancer connection and beyond

“…PML can associate with heterochromatin region PADs, where it induces heterochromatic organization in PADs and induces pro-metastatic gene expression in subregions of PADs depleted of PML. Such a function of nucleoplasmic PML was observed in triple-negative breast cancer cells, suggesting a potential role of nucleoplasmic PML in gene regulation [ 66 ].…”

History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies

“…Indeed, PML associates to chromatin near highly active transcriptional loci, at promotor regions but also in gene-poor regions [153]. These loci do not localize at PML NBs, suggesting a role of the nucleoplasmic fraction of the protein [154,155]. PML NBs also recruit and control the post-translational modifications of numerous proteins at their inner core.…”