Nguyen Lily L, Watson Zachary L, Ortega Raquel, Woodruff Elizabeth R, Jordan Kimberly R, Iwanaga Ritsuko, Yamamoto Tomomi M, Bailey Courtney A, Jeong Abigail D, Guntupalli Saketh R, Behbakht Kian, Gbaja Veronica, Arnoult Nausica, Chuong Edward B, Bitler Benjamin G
Molecular Cellular Developmental Biology, The University of Colorado Boulder, Boulder, CO 80309, USA.
Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, 80045.
bioRxiv. 2023 Feb 23:2023.02.23.529773. doi: 10.1101/2023.02.23.529773.
Euchromatic histone lysine methyltransferases 1 and 2 (EHMT1/2), which catalyze demethylation of histone H3 lysine 9 (H3K9me2), contribute to tumorigenesis and therapy resistance through unknown mechanisms of action. In ovarian cancer, EHMT1/2 and H3K9me2 are directly linked to acquired resistance to poly-ADP-ribose polymerase (PARP) inhibitors and are correlated with poor clinical outcomes. Using a combination of experimental and bioinformatic analyses in several PARP inhibitor resistant ovarian cancer models, we demonstrate that combinatory inhibition of EHMT and PARP is effective in treating PARP inhibitor resistant ovarian cancers. Our studies show that combinatory therapy reactivates transposable elements, increases immunostimulatory dsRNA formation, and elicits several immune signaling pathways. Our studies show that both single inhibition of EHMT and combinatory inhibition of EHMT and PARP reduces tumor burden, and that this reduction is dependent on CD8 T cells. Together, our results uncover a direct mechanism by which EHMT inhibition helps to overcome PARP inhibitor resistance and shows how an epigenetic therapy can be used to enhance anti-tumor immunity and address therapy resistance.
常染色质组蛋白赖氨酸甲基转移酶1和2（EHMT1/2）催化组蛋白H3赖氨酸9（H3K9me2）的去甲基化，通过未知的作用机制促进肿瘤发生和治疗耐药性。在卵巢癌中，EHMT1/2和H3K9me2与对聚ADP核糖聚合酶（PARP）抑制剂的获得性耐药直接相关，并与不良临床结果相关。在几种PARP抑制剂耐药的卵巢癌模型中，通过实验分析和生物信息学分析相结合，我们证明联合抑制EHMT和PARP对治疗PARP抑制剂耐药的卵巢癌有效。我们的研究表明，联合治疗可重新激活转座元件，增加免疫刺激双链RNA的形成，并引发多种免疫信号通路。我们的研究表明，单独抑制EHMT以及联合抑制EHMT和PARP均可减轻肿瘤负担，且这种减轻依赖于CD8 T细胞。总之，我们的结果揭示了EHMT抑制有助于克服PARP抑制剂耐药性的直接机制，并展示了表观遗传疗法如何用于增强抗肿瘤免疫力和解决治疗耐药性问题。
