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SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma

Davide Martino Coda1, Marcello Francesco Lingua, Deborah Morena

  • 1a Department of Oncology ; University of Turin ; Turin , Italy.

Cell Cycle (Georgetown, Tex.)
|February 4, 2015
PubMed

Insights

MicroRNA-206 (miR-206) induces differentiation in rhabdomyosarcoma cells by regulating SMYD1 and G6PD. Combining miR-206 with DCA enhances tumor suppression by reprogramming cell metabolism and epigenetics.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma where cells resemble immature muscle cells (myoblasts) but fail to differentiate.
  • MicroRNA-206 (miR-206) is downregulated in RMS but can induce differentiation by targeting numerous genes.
  • Understanding miR-206's downstream effectors is crucial for developing targeted therapies for RMS.

Purpose of the Study:

  • To investigate the roles of SMYD1 and G6PD, two key targets of miR-206, in RMS cell differentiation and proliferation.
  • To explore the potential of combining miR-206 with metabolic modulators like dichloroacetate (DCA) for enhanced therapeutic effects.

Main Methods:

  • Silencing and overexpression of SMYD1 and G6PD in RMS cell lines (ERMS, ARMS).
  • Assessment of myogenic differentiation markers, anchorage independence, and cell proliferation.
  • Treatment with miR-206 mimics and dichloroacetate (DCA), followed by analysis of cell growth inhibition and pyruvate dehydrogenase (PDH) activity.

Main Results:

  • SMYD1 is essential for muscle gene activation and differentiation, but not for miR-206's proliferative block.
  • G6PD is a direct miR-206 target; its silencing impairs proliferation, while overexpression doesn't affect miR-206's pro-differentiation role.
  • DCA enhances miR-206-induced growth inhibition and sustains it, suggesting metabolic reprogramming contributes to tumor suppression.

Conclusions:

  • miR-206 orchestrates both epigenetic (via SMYD1) and metabolic (via G6PD) reprogramming in RMS differentiation.
  • Targeting cancer metabolism alongside differentiation induction holds promise for RMS therapy.
  • Combination therapy with miR-206 and DCA shows potential for sustained tumor growth inhibition.
Keywords:
DCA, DichloroacetateDHEA, DehydroepiandrosteroneG6PD, Glucose 6 Phosphate DehydrogenaseHMT, Histone MethylTransferaseMREs, MicroRNA Responsive ElementsMRFs, Myogenic Regulatory FactorsPDH, Pyruvate DehydrogenasePDK, Pyruvate Dehydrogenase KinasePPP, Pentose Phosphate PathwayRMS, RhabdomyosarcomaRhabdomyosarcomaSMYD1, SET and MYND domain-containing protein 1TCA cycle, TriCarboxylic Acid cycledifferentiation therapymetabolism and cancermiR-206myomiRs, muscle-specific microRNAs

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