Scholarlink

<p>Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we apply in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits include genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase <i>USP22</i> confers cisplatin-etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of <i>USP22</i> re-sensitizes tumors to chemotherapy. USP22 loss increases gene body histone H2AK119 monoubiquitylation at key regulators of neuronal differentiation and suppresses neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflects attenuated DNA damage-driven phosphorylation events and apoptosis, in conjunction with increased expression of glycolysis and hypoxia-related genes. Glycolysis program upregulation may reflect a targetable vulnerability, as inhibition of GLUT1 re-sensitizes USP22-null tumors to chemotherapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Loss of the USP22 deubiquitylase confers resistance to chemotherapy in small cell lung cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

查看全文
  • Scott Best,
  • Daniel S. Hippe,
  • Eli Grunblatt,
  • Jackson Fatherree,
  • Pritha Chanana,
  • Feinan Wu,
  • Richard Ivey,
  • Jacob J. Kennedy,
  • David Sokolov,
  • Ali Ibrahim,
  • Haodong Xu,
  • Raymond J. Monnat Jr,
  • Lucas B. Sullivan,
  • Patrick Paddison,
  • Amanda G. Paulovich,
  • David MacPherson

摘要

Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we apply in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits include genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase USP22 confers cisplatin-etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of USP22 re-sensitizes tumors to chemotherapy. USP22 loss increases gene body histone H2AK119 monoubiquitylation at key regulators of neuronal differentiation and suppresses neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflects attenuated DNA damage-driven phosphorylation events and apoptosis, in conjunction with increased expression of glycolysis and hypoxia-related genes. Glycolysis program upregulation may reflect a targetable vulnerability, as inhibition of GLUT1 re-sensitizes USP22-null tumors to chemotherapy.