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The OTUD6B-LIN28B-MYC axis determines the proliferative state in multiple myeloma

Carmen Paulmann1,2, Ria Spallek1,2, Oleksandra Karpiuk1,2

  • 1Department of Medicine III, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

The EMBO Journal
|September 5, 2022
PubMed

Insights

Deubiquitylases (DUBs) like OTUD6B stabilize oncogenic proteins in multiple myeloma. Inhibiting OTUD6B or its substrate LIN28B halts cancer growth and improves patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Deubiquitylases (DUBs) are key regulators of protein stability and are implicated in cancer.
  • Multiple myeloma is a malignancy dependent on the ubiquitin proteasome system, presenting a potential vulnerability.
  • Targeting DUBs offers a strategy to destabilize oncoproteins, including those currently considered undruggable.

Purpose of the Study:

  • To identify DUB vulnerabilities in multiple myeloma.
  • To investigate the role of OTUD6B in driving the G1/S cell cycle transition in multiple myeloma.
  • To elucidate the OTUD6B-LIN28B-MYC axis in multiple myeloma pathogenesis.

Main Methods:

  • Screening for DUB vulnerabilities in multiple myeloma cell lines.
  • Identifying cell cycle-specific substrates of OTUD6B.
  • Assessing the impact of OTUD6B and LIN28B silencing on multiple myeloma growth in vivo.
  • Correlating OTUD6B expression with patient outcomes in symptomatic multiple myeloma.

Main Results:

  • OTUD6B was identified as an oncogene driving the G1/S transition in multiple myeloma.
  • LIN28B was validated as a cell cycle-specific substrate of OTUD6B, and its stabilization promotes MYC expression.
  • Silencing OTUD6B or LIN28B significantly inhibited multiple myeloma outgrowth in vivo.
  • High OTUD6B expression correlated with disease progression and adverse outcomes in multiple myeloma patients.

Conclusions:

  • OTUD6B acts as an oncogene in multiple myeloma by stabilizing LIN28B, which drives MYC expression and G1/S transition.
  • The OTUD6B-LIN28B axis represents a novel therapeutic vulnerability in multiple myeloma.
  • OTUD6B may mediate the transition from MGUS to symptomatic multiple myeloma and serves as a prognostic marker.
Keywords:
RNA binding proteinscell cycledeubiquitylasesmultiple mylomaubiquitin

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