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

Sep 21, 2026

Uploaded by Hazel

PML1 is identified as the most abundant PML isoform across breast cancer subtypes and its expression is linked to poor prognosis in estrogen receptor-positive (ER+) tumors. PML depletion reduces proliferation, invasion, and stemness, whereas heterologous PML1 re-expression restores these phenotypes and promotes tumor growth and resistance to fulvestrant in mice. Mechanistically, PML1 coordinates with ER and Myc at promoters and recruits WDR5 and H3K4 methyltransferase complexes to sustain H3K4me3, sustaining breast cancer stem cell gene programs and tumorsphere formation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

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Introduction

PML function and nuclear bodies

Rationale: tumor-suppressor vs oncogenic roles of PML

Study objective and key findings

[www.nature.com/cdd](www.nature.com/cdd) ARTICLE OPEN The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer Chun-Peng Pai 1, Han Wang 1, Darcie D. Seachrist2,3, Neel Agarwal 1, Joshua A. Adams 1, Zhenghao Liu 1, Ruth A. Keri2,3,4, Kaixiang Cao1,3, William P. Schiemann 1,3 and Hung-Ying Kao1,3 ✉ © The Author(s) 2024 | | The 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 tofulvestrant, 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 promotersin 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 loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Signiﬁcantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant’s anticancer activity. Our ﬁndings challenge the conventional understanding of PML as a tumor suppressor, redeﬁne its role as a promoter of tumor growth in breast cancer, and offer new | | | --- | --- | --- | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | insights into the unique roles of PML isoforms in breast cancer. | | | | | Cell Death & Differentiation (2024) 31:768–778; [https://doi.org/10.1038/s41418-024-01294-6](https://doi.org/10.1038/s41418-024-01294-6) | | | | | | INTRODUCTION The PML protein has diverse cellular functions, including regulating cell-cycle progression, DNA damage responses, and transcription; it also plays important roles in governing immunity, metabolism, and tumorigenesis [1–7] . PML protein is primarily localized in the nucleoplasm and DNA-free sub-nuclear compartments known as PML nuclear bodies (NBs) [8–10], which may indirectly regulate transcription by sequestering transcription factors or serving as a platform protein for transcription factor modiﬁcation [11, 12] . Several studies have suggested that PML binds to chromatin, indicating a direct role in transcriptional regulation [6, 13, 14] . However, a systematic analysis of the global PML-bound promoters is lacking. The notion that PML is a tumor suppressor gene was mainly based on studies of the PML4 isoform [12, 15–17] and earlier clinical investigations [17] . Recent studies have revealed a more complex role for PML in cancer. Knockdown of PML inhibits the proliferation of estrogen receptor-positive (ER+) breast cancer [18] and ovarian cancer cells [19] and reduces tumor growth in mouse xenograft models of triple-negative breast cancer (TNBC)

FAQs

What role does PML1 play in ER+ breast cancer compared with other PML isoforms?

PML1 is the most abundant PML isoform in breast cancer and its increased expression correlates with poor prognosis in ER+ tumors. PML1 loss reduces proliferation, invasion, and stemness, while PML1 re-expression restores these effects.

How does PML1 influence breast cancer stemness and therapy response?

PML depletion suppresses breast cancer stemness, whereas heterologous PML1 expression promotes stemness, tumor growth, and resistance to fulvestrant in a mouse model. PML1 is therefore linked to maintenance of cancer stem cell programs.

What mechanistic connection links PML1 to H3K4me3 and stem cell gene programs?

PML1 establishes a novel association with WDR5, a component of H3K4 methyltransferase complexes that catalyze H3K4me1 and H3K4me3. Loss of PML1 reduces H3K4me3 at promoters, while PML1 restores H3K4me3 and recruitment of WDR5/MLL1/MLL2, sustaining BCSC-associated gene expression.

Sep 21, 2026

Uploaded by Hazel