Epigenetic regulator Smarcd3 is required for established tumor growth in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by aggressive metastasis and resistance to therapy, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and malignant features of disease. Given the central role for epigenetic regulation in development, we hypothesized that epigenetic factors may be required to sustain the self-renewal of pancreatic cancer cells. Here, we used a functional screen to identify Smarcd3, a component of the SWI/SNF (BAF) nucleosome remodeling complex, as a novel functional dependency in PDAC. SWI/SNF coordinates context-specific gene regulation in development and is frequently dysregulated in cancer. However, Smarcd3 has not been linked to functions in PDAC and represents a new epigenetic mediator of cancer function. We found that Smarcd3 was uniquely up-regulated in PDAC stem cells and was required for the in vivo propagation of mouse and patient-derived tumors. Furthermore, using integrated RNA-seq, ChIP-seq, and network analysis we showed that Smarcd3 regulates global SWI/SNF binding and histone acetylation, driving the epigenetic regulation of lipid metabolic programs. Specifically, we found that Smarcd3 regulated genes converging on fatty acid metabolism, which has been directly implicated in stem signaling in PDAC. Collectively, these data identify Smarcd3 as a critical novel dependency and epigenetic regulator of lipid metabolism pancreatic cancer. Overall design: ChIP-seq for Smarca4, Arid1a, H3K4me, H3K4me3 and H3K27ac in KPf/fC cells transduced with shControl or shSmarcd3; RNA-seq in KPf/fC cells transduced with shControl or shSmarcd3.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是一种以侵袭性转移和治疗抵抗为特征的疾病，给临床诊疗带来了极大挑战。随着癌症进展，发育信号常发生异常再激活，驱动癌细胞自我更新并促成疾病的恶性表型。鉴于表观遗传调控在发育过程中的核心作用，我们推测表观遗传因子可能是维持胰腺癌细胞自我更新所必需的。本研究通过功能筛选，鉴定出SWI/SNF（BAF）核小体重塑复合物的组分Smarcd3是胰腺导管腺癌的新型功能性依赖基因。SWI/SNF复合物在发育过程中协调情境特异性基因调控，且在癌症中常发生失调。然而，此前尚无研究将Smarcd3与胰腺导管腺癌的功能联系起来，其代表了一种新的癌症功能表观遗传调控介质。我们发现，Smarcd3在胰腺导管腺癌干细胞中特异性上调，且是小鼠及患者来源肿瘤体内增殖所必需的。此外，通过整合RNA测序（RNA-seq）、染色质免疫共沉淀测序（ChIP-seq）及网络分析，我们证实Smarcd3可调控全局SWI/SNF结合与组蛋白乙酰化，驱动脂质代谢程序的表观遗传调控。具体而言，我们发现Smarcd3调控的基因集中于脂肪酸代谢通路，而该通路已被证实与胰腺导管腺癌的干细胞信号直接相关。综上，本研究数据证实Smarcd3是胰腺导管腺癌中至关重要的新型功能性依赖基因及脂质代谢表观调控因子。实验整体设计：在转染对照短发夹RNA（shControl）或靶向Smarcd3的短发夹RNA（shSmarcd3）的KPf/fC细胞中，针对Smarca4、Arid1a、H3K4me、H3K4me3及H3K27ac进行染色质免疫共沉淀测序（ChIP-seq）；同时在转染shControl或shSmarcd3的KPf/fC细胞中进行RNA测序（RNA-seq）。