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HOXB13 controls cell state through super-enhancers.

Paul-Joseph Aspuria1, Dong-Joo Cheon1, Maricel C Gozo1

  • 1Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Experimental Cell Research
|May 8, 2020
PubMed
Summary

High HOXB13 levels fuel aggressive pediatric tumors like malignant rhabdoid tumors by blocking stem cell differentiation. Reducing HOXB13 promotes tumor cell differentiation into bone, revealing a key role in cancer progression.

Keywords:
AdipogenesisDifferentiationHOXB13HomeoboxMesenchymal stem cellsMyogenesisOsteogenesisRhabdoid tumorSarcomaSuper-enhancer

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Area of Science:

  • Oncology
  • Developmental Biology
  • Molecular Biology

Background:

  • The transcription factor HOXB13 is expressed in various cancers, but its precise role in tumor development is not fully understood.
  • High HOXB13 levels are found in poorly differentiated pediatric tumors, notably malignant rhabdoid tumors (MRT), an aggressive childhood cancer.

Purpose of the Study:

  • To investigate the role of HOXB13 in the tumorigenesis and differentiation of malignant rhabdoid tumors.
  • To elucidate the molecular mechanisms by which HOXB13 influences cancer cell behavior and mesenchymal stem cell differentiation.

Main Methods:

  • Utilized a xenograft model of rhabdoid tumor to assess the effects of HOXB13 knockout and knockdown on tumor growth and cell differentiation.
  • Overexpressed HOXB13 in mesenchymal progenitor cells to evaluate its impact on adipogenic, myogenic, and osteogenic differentiation.
  • Investigated HOXB13 binding to super-enhancer regions using molecular techniques to identify regulated genes involved in differentiation and tumorigenesis.

Main Results:

  • HOXB13 knockout significantly reduced rhabdoid tumor growth in a xenograft model.
  • Partial HOXB13 knockdown induced differentiation of tumor cells towards a bone-forming phenotype.
  • Overexpression of HOXB13 in mesenchymal progenitor cells inhibited key differentiation pathways (adipogenic, myogenic, osteogenic).
  • HOXB13 was found to bind super-enhancer regions, regulating genes critical for differentiation and tumor development.

Conclusions:

  • HOXB13 promotes the malignancy of rhabdoid tumors by inhibiting mesenchymal stem cell differentiation.
  • HOXB13 acts as a crucial regulator in pediatric cancer, potentially by interfering with normal developmental processes.
  • Targeting HOXB13 may offer a therapeutic strategy for aggressive pediatric tumors by restoring differentiation pathways.