Phosphorylated DHX9 inhibited the progression of lung adenocarcinoma by regulating R-loops mediated DNA damage

Lei Wu1, Shengyu Wang2, Xin Diao2

  • 1Department of Medical Records Managerment and Date Center, The First Affiliated Hospital of Xi'an Medical University, China.

Insights

Phosphorylated DHX9 inhibits lung adenocarcinoma by increasing DNA damage and R-loops, suppressing cell proliferation. This mechanism involves DHX9

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • DHX9 is implicated in cancer progression.
  • The role of phosphorylated DHX9 in lung adenocarcinoma is unclear.
  • Understanding DHX9's interactions with R-loops and DNA damage is crucial.

Purpose of the Study:

  • To investigate the mechanism by which phosphorylated DHX9 inhibits lung adenocarcinoma.
  • To elucidate the interplay between DHX9, phosphorylated DHX9, R-loops, and DNA damage.
  • To assess the impact of DHX9 modulation on lung cancer cell behavior.

Main Methods:

  • Utilized various cell lines (PC-9, 2BS) with genetic manipulations (siDHX9, OE-DHX9, OE-PKA, specific mutants).
  • Employed molecular biology techniques: qRT-PCR, Western Blot (WB), EdU/CCK-8, TUNEL, flow cytometry, comet assay, CldU/IdU, and DRIP-qPCR.
  • Validated findings in nude mice xenograft models.

Main Results:

  • DHX9 expression is elevated in lung cancer.
  • siDHX9 reduced proliferation and increased apoptosis, DNA damage, and R-loops.
  • OE-DHX9 showed opposite effects.
  • Phosphorylation mimic (OE-PKA) increased R-loops and DNA damage, while non-phosphorylatable mutant (DHX9-S279A) decreased them.
  • In vivo studies confirmed DHX9's role in tumor suppression via DNA damage and R-loop induction.

Conclusions:

  • Phosphorylated DHX9 enhances DNA damage by impeding R-loop resolution.
  • This process ultimately inhibits lung adenocarcinoma cell proliferation.
  • DHX9 phosphorylation represents a potential therapeutic target for lung cancer.

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