HELLS, a chromatin remodeler is highly expressed in pancreatic cancer and downregulation of it impairs tumor growth and sensitizes to cisplatin by reexpressing the tumor suppressor TGFBR3.
HELLS, a chromatin remodeler is highly expressed in pancreatic cancer and downregulation of it impairs tumor growth and sensitizes to cisplatin by reexpressing the tumor suppressor TGFBR3.
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作者：
Hou X;Yang L;Wang K;Zhou Y;Li Q;Kong F;Liu X;He J
胰腺癌（PC）是消化系统恶性程度最高的癌症类型，预后较差。顺铂等化疗是诊断患有晚期或转移性疾病的 PC 患者的最后机会。深入了解 PC 肿瘤发生的分子机制并确定最佳生物标志物来估计化疗敏感性对于 PC 治疗至关重要。人们发现染色质重塑因子 HELLS 在多种癌症中通过表观遗传途径调节各种肿瘤抑制因子。我们通过蛋白质印迹和免疫组织化学染色分析了临床样本中的 HELLS 表达。接下来，我们确定了 HELLS 敲低后肿瘤生长和顺铂敏感性的变化，并通过 RNA 测序、染色质免疫沉淀以及功能获得和丧失检测探索了 PC 中 HELLS 的下游介质。我们发现HELLS在PC组织中表达上调，与晚期临床分期和不良预后相关，并且HELLS的敲低导致肿瘤生长停滞和对顺铂的敏感性增加。从机制上讲，肿瘤抑制因子 TGFBR3 在 HELLS 敲除后显着重新表达；相反，损害 TGFBR3 可以挽救 PC 细胞中 HELLS 敲低介导的效应。因此，我们的数据提供证据表明，HELLS 可以作为潜在的癌基因和合适的生物标志物，通过表观遗传学沉默 PC 中的肿瘤抑制因子 TGFBR3 来评估化疗敏感性。我们发现胰腺癌高度表达染色质重塑剂 HELLS，其下调会导致胰腺癌生长减少并提高对顺铂的敏感性。 RNA-seq、ChIP 和功能测定用于探索 HELLS 的下游机制，发现肿瘤抑制因子 TGFBR3 负责 HELLS 敲低介导的胰腺癌细胞效应。
Pancreatic cancer (PC) is the most malignant cancer type in the digestive system with a poor prognosis. Chemotherapy such as cisplatin is the last chance for PC patients diagnosed with advanced or metastatic disease. Obtaining a deep understanding of the molecular mechanism underlying PC tumorigenesis and identifying optimal biomarkers to estimate chemotherapy sensitivity are essential for PC treatment. The chromatin remodeler HELLS was found to regulate various tumor suppressors through an epigenetic pathway in several cancers. We analyzed HELLS expression in clinical samples by Western blotting and immunohistochemical staining. Next, we identified the variation in tumor growth and cisplatin sensitivity after knockdown of HELLS and explored the downstream mediators of HELLS in PC via RNA‐seq, chromatin immunoprecipitation, and gain‐ and loss‐of‐function assays. We found that HELLS is upregulated in PC tissues and correlates with advanced clinical stage and a poor prognosis, and the knockdown of HELLS leads to tumor growth arrest and increased sensitivity to cisplatin. Mechanistically, the tumor suppressor TGFBR3 is markedly reexpressed after HELLS knockdown; conversely, compromising TGFBR3 rescues HELLS knockdown‐mediated effects in PC cells. Thus, our data provide evidence that HELLS can serve as a potential oncogene and suitable biomarker to evaluate chemotherapy sensitivity via epigenetically silencing the tumor suppressor TGFBR3 in PC. We found that pancreatic cancer highly expressed a chromatin remodeler, HELLS, and downregulation of it led to decreased growth of pancreatic cancer and improved sensitivity to cisplatin. RNA‐seq, ChIP, and functional assays were used to explore the downstream mechanisms of HELLS and found that the tumor suppressor TGFBR3 was responsible for HELLS knockdown‐mediated effects in pancreatic cancer cells.
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