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The splicing factor QKI inhibits metastasis by modulating alternative splicing of E-Syt2 in papillary thyroid

Mengya Zhao1, Yu Jin2, Zhongyi Yan3

  • 1Department of Head and Neck Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University & The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center Nanjing, Nanjing Medical University, Nanjing, China; Wuxi People's Hospital, Wuxi Medical Center Nanjing & Department of Immunology, School of Basic Medical Science & Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China; The Affiliated Huai'an No. 1 People's Hospital, Nanjing Medical University, Nanjing, China.

Cancer Letters
|September 21, 2024
PubMed

Insights

Quaking protein (QKI) downregulation promotes papillary thyroid carcinoma (PTC) growth and metastasis by altering splicing. Targeting QKI or its related splicing events may offer new therapeutic strategies for PTC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Alternative splicing (AS) is implicated in cancer development and progression.
  • Aberrant AS events contributing to papillary thyroid carcinoma (PTC) metastasis are not well understood.

Purpose of the Study:

  • To investigate the role of the splicing factor quaking protein (QKI) in PTC metastasis.
  • To elucidate the molecular mechanisms linking QKI to PTC progression.

Main Methods:

  • Analysis of QKI expression in PTC patient samples and correlation with survival.
  • In vitro and in vivo functional studies to assess the impact of QKI on PTC cell behavior.
  • Mechanistic investigations involving alternative splicing of extended synaptotagmin 2 (E-Syt2) and interactions with long non-coding RNA eosinophil granule ontogeny transcript (EGOT).

Main Results:

  • QKI was significantly downregulated in PTC and associated with poor patient outcomes.
  • Reduced QKI expression enhanced PTC cell growth and metastasis.
  • Low QKI levels induced exon 14 retention of E-Syt2, generating an oncogenic E-Syt2 long isoform (E-Syt2L).
  • Overexpressed EGOT suppressed QKI activity by inhibiting USP25-mediated deubiquitination and degradation.

Conclusions:

  • QKI functions as a tumor suppressor in PTC metastasis.
  • The QKI/E-Syt2 splicing axis represents a novel mechanism driving PTC metastasis.
  • Targeting aberrant splicing events, particularly those involving QKI, presents a potential therapeutic avenue for PTC.
Keywords:
Alternative splicingE-Syt2EGOTPapillary thyroid carcinomaQKIUSP25

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