组蛋白甲基转移酶KMT2D在前列腺癌（PCa）中扮演重要的人类癌基因角色。炎症反应和细胞因子信号的失调与癌症进展有关。此外，白细胞介素6（IL-6）是一种具有多向性的细胞因子，可促进PCa的进展，然而KMT2D和IL-6在PCa中的关联仍不清楚。使用细胞计数试剂盒-8（CCK-8）、EdU掺入、划痕愈合和凋亡试验，在体外测定了PCa细胞的增殖潜能、迁移潜能和凋亡。将PCa细胞培养在KMT2D缺失细胞的条件培养基中，会导致细胞增殖和迁移能力下降以及凋亡诱导。细胞因子分析表明，在条件培养基中，白细胞介素6（IL-6）是受影响最大的细胞因子。KMT2D敲失显著降低了PCa细胞中IL-6的表达。而通过沉默IL-6R表达，也会导致细胞增殖和迁移能力下降以及凋亡诱导发生。采用免疫组化（IHC）和定量逆转录-聚合酶链反应（qRT-PCR），验证了KMT2D和IL-6在PCa组织样本中的正相关性。染色质免疫共沉淀（ChIP）-PCR表明，KMT2D和H3K4me1占据了IL-6增强子区域，从而直接调节了IL-6的表达。本研究揭示了KMT2D敲下通过下调旁分泌的IL-6信号通路来抑制前列腺癌的进展。这些结果提示KMT2D可能是PCa治疗的潜在新靶点。Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Histone methyltransferase KMT2D plays a critical role as a human oncogene in prostate cancer (PCa). Dysregulated inflammatory responses and cytokine signaling are implicated in cancer progression. Furthermore, interleukin 6 (IL-6) is a pleiotropic cytokine that contributes to PCa progression; however, the association between KMT2D and IL-6 in PCa remains unclear. PCa cell proliferative potential, migratory potential, and apoptosis in vitro were determined using cell counting kit-8 (CCK-8), EdU incorporation, wound healing, and apoptosis assays. Proliferation and migratory potential were impaired and apoptosis was induced in PCa cells cultured with the conditioned medium from KMT2D-depleted cells. Cytokine array analysis showed that IL-6 was the most affected cytokine in the conditioned media. KMT2D knockdown significantly downregulated the expression of IL-6 in PCa cells. What's more, proliferation and migration were also impaired and apoptosis was also induced by silencing IL-6R expression. Immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were performed to validate the positive correlation between KMT2D and IL-6 in PCa tissue samples. Chromatin immunoprecipitation (ChIP)-PCR demonstrated that KMT2D and H3K4me1 occupied IL-6 enhancer regions and therefore, directly regulated IL-6 expression. The present study revealed that the KMT2D knockdown suppressed prostate cancer progression through the downregulation of paracrine IL-6 signaling. These results suggest that KMT2D could be regarded as a potential new target for PCa therapy.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.