Myeloma Center, Division of Hematology/Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
College of Medicine, Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Curr Res Transl Med. 2021 Jul;69(3):103290. doi: 10.1016/j.retram.2021.103290. Epub 2021 Apr 22.
Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.
表观遗传失调越来越被认为是多发性骨髓瘤（MM）的一个致病因素。特别是三甲基化 H3 赖氨酸 27（H3K27me3），由 PHD 手指蛋白 19（PHF19）催化，PHF19 是多梳抑制复合物 2（PRC2）的一个亚基，最近被证明是多发性骨髓瘤肿瘤发生的关键介质。PHF19 在 MM 中的过表达与更差的临床结局相关。然而，尽管越来越多的证据表明 PHF19 过表达在 MM 致癌作用中发挥关键作用，但下游机制仍有待阐明。在本研究中，我们使用 PHF19 的功能敲低（KD）来研究 PHF19 的生物学作用，并表明 PHF19KD 导致体外和体内肿瘤生长减少。PHF19KD 后主要癌症相关蛋白（如 bcl2、myc 和 EGR1）的表达降低，进一步强调了 PHF19 在 MM 生物学中的作用。此外，我们的研究结果强调了 PHF19 过表达的预后影响，其与较差的生存显著相关。总的来说，我们的研究强调了靶向 PHF19-PRC2 复合物将为新型 MM 治疗开辟途径的前提。
