HOXB13 controls cell state through super-enhancers

Paul-Joseph Aspuria; Dong-Joo Cheon; Maricel C Gozo; Jessica A Beach; Maria Sol Recouvreux; Ann E Walts; Beth Y Karlan; Sandra Orsulic

doi:10.1016/j.yexcr.2020.112039

HOXB13 controls cell state through super-enhancers

Exp Cell Res. 2020 Aug 1;393(1):112039. doi: 10.1016/j.yexcr.2020.112039. Epub 2020 May 4.

Authors

Paul-Joseph Aspuria¹, Dong-Joo Cheon¹, Maricel C Gozo¹, Jessica A Beach¹, Maria Sol Recouvreux², Ann E Walts³, Beth Y Karlan⁴, Sandra Orsulic⁵

Affiliations

¹ Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
² Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁴ Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Women's Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, 90095, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: sorsulic@mednet.ucla.edu.

PMID: 32376288
DOI: 10.1016/j.yexcr.2020.112039

Abstract

Expression of the homeodomain transcription factor HOXB13 has been demonstrated in several malignancies but its role in tumorigenesis remains elusive. We observed high levels of HOXB13 in poorly differentiated pediatric tumors including a highly aggressive childhood neoplasm - malignant rhabdoid tumor. In a xenograft model of rhabdoid tumor, knockout of HOXB13 diminished tumor growth while partial knockdown of HOXB13 promoted differentiation of tumor cells into bone. These results suggest that HOXB13 enhances rhabdoid malignancy by interfering with mesenchymal stem cell differentiation. Consistent with this hypothesis, overexpression of HOXB13 in mesenchymal progenitor cells inhibited adipogenic, myogenic, and osteogenic differentiation. Mechanistically, we demonstrated that HOXB13 binds to super-enhancer regions regulating genes involved in differentiation and tumorigenesis.

Keywords: Adipogenesis; Differentiation; HOXB13; Homeobox; Mesenchymal stem cells; Myogenesis; Osteogenesis; Rhabdoid tumor; Sarcoma; Super-enhancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bone and Bones / metabolism
Cell Differentiation / genetics
Cell Differentiation / physiology*
Gene Expression Regulation / genetics
Genes, Homeobox / genetics
Homeodomain Proteins / metabolism*
Humans
Mesenchymal Stem Cells / cytology*
Osteogenesis / physiology*
Transcription Factors / metabolism

Substances

HOXB13 protein, human
Homeodomain Proteins
Transcription Factors

Grants and funding

P30 CA016042/CA/NCI NIH HHS/United States