Miz1 promotes KRAS-driven lung tumorigenesis by repressing the protocadherin Pcdh10

Jing Yang, Changchun Hou, Huashan Wang, Edith A. Perez, Hanh Chi Do-Umehara, Huali Dong, Vinothini Arunagiri, Fangjia Tong, Michelle Van Scoyk, Minsu Cho, Xinyi Liu, Xiaodong Ge, Robert A. Winn, Karen M. Ridge, Xiaowei Wang, Navdeep S. Chandel, Jing Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Targeting KRAS-mutated non-small-cell lung cancer (NSCLC) remains clinically challenging. Here we show that loss of function of Miz1 inhibits lung tumorigenesis in a mouse model of oncogenic KRAS-driven lung cancer. In vitro, knockout or silencing of Miz1 decreases cell proliferation, clonogenicity, migration, invasion, or anchorage-independent growth in mutant (MT) KRAS murine or human NSCLC cells but has unremarkable impact on non-tumorigenic cells or wild-type (WT) KRAS human NSCLC cells. RNA-sequencing reveals Protocadherin-10 (Pcdh10) as the top upregulated gene by Miz1 knockout in MT KRAS murine lung tumor cells. Chromatin immunoprecipitation shows Miz1 binding on the Pcdh10 promoter in MT KRAS lung tumor cells but not non-tumorigenic cells. Importantly, silencing of Pcdh10 rescues cell proliferation and clonogenicity in Miz1 knockout/knockdown MT KRAS murine or human tumor cells, and rescues allograft tumor growth of Miz1 knockout tumor cells in vivo. Miz1 is upregulated in MT KRAS lung tumor tissues compared with adjacent non-involved tissues in mice. Consistent with this, Miz1 is upregulated while Pcdh10 is downregulated in human lung adenocarcinomas (LUAD) compared with normal tissues, and high Miz1 levels or low Pcdh10 levels are associated with poor survival in lung cancer patients. Furthermore, the Miz1 signature is associated with worse survival in MT but not WT KRAS LUAD, and Pcdh10 is downregulated in MT compared to WT KRAS LUAD. Taken together, our studies implicate the Miz1/Pcdh10 axis in oncogenic KRAS-driven lung tumorigenesis.

Original languageEnglish (US)
Article number216025
JournalCancer Letters
Volume555
DOIs
StatePublished - Feb 28 2023

Keywords

  • Gene regulation
  • KRAS
  • Miz1
  • Non-small cell lung cancer
  • Pcdh10

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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