<br>PML1-WDR5轴调节H3K4me3标记并促进雌激素受体阳性乳腺癌的干细胞性,Cell Death and Differentiation

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PML1-WDR5轴调节H3K4me3标记并促进雌激素受体阳性乳腺癌的干细胞性
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2024-04-16 , DOI: 10.1038/s41418-024-01294-6
Chun-Peng Pai ₁ , Han Wang ₁ , Darcie D Seachrist _{2,

3} , Neel Agarwal ₁ , Joshua A Adams ₁ , Zhenghao Liu ₁ , Ruth A Keri _{2,

3,

4} , Kaixiang Cao _{1,

3} , William P Schiemann _{1,

3} , Hung-Ying Kao _{1,

3}

Affiliation

PML前体 mRNA 的选择性剪接产生各种PML同工型，但它们在乳腺癌细胞中的表达谱仍然未知。我们发现 PML1 是所有乳腺癌亚型中最丰富的亚型，其表达与雌激素受体阳性 (ER+) 乳腺癌的不良预后相关。在小鼠模型中， PML耗竭会减少细胞增殖、侵袭和干性，而异源 PML1 表达会增强这些过程，并促进肿瘤生长和对氟维司群（FDA 批准的治疗 ER+ 乳腺癌的药物）的耐药性。此外，PML1（而不是众所周知的肿瘤抑制亚型 PML4）可以挽救PML敲低细胞的增殖。 ChIP-seq 分析揭示了 PML、ER 和 Myc 结合启动子之间的显着重叠，表明它们对靶基因表达的协调调节，包括乳腺癌干细胞 (BCSC) 中涉及的基因，例如JAG1 、 KLF4 、 YAP1 、 SNAI1和MYC 。 PML的缺失会降低 BCSC 相关基因的表达，而外源性 PML1 的表达会提高其表达。一致地，PML1 在PML耗尽的细胞中恢复 PML 与这些启动子的关联。我们发现了 PML1 和 WDR5 之间的新关联，WDR5 是催化 H3K4me1 和 H3K4me3 的 H3K4 甲基转移酶 (HMT) 复合物的关键成分。 ChIP-seq 分析表明， PML1的缺失会减少许多基因座中的 H3K4me3，包括 BCSC 相关基因启动子。此外，在PML耗尽的细胞中，PML1（而非 PML4）在这些启动子上重新建立了 H3K4me3 标记。值得注意的是，PML1 对于将 WDR5、MLL1 和 MLL2 招募到这些基因启动子至关重要。通过敲低或抑制剂使 WDR5 失活，可以模拟 PML1 丢失的影响，减少 BCSC 相关基因表达和肿瘤球形成，并增强氟维司群的抗癌活性。我们的研究结果挑战了 PML 作为肿瘤抑制因子的传统认识，重新定义了其作为乳腺癌肿瘤生长促进剂的作用，并为 PML 亚型在乳腺癌中的独特作用提供了新的见解。

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

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 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 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.

更新日期：2024-04-16

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