The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

Narendra Bharathy, Noah E. Berlow, Eric Wang, Jinu Abraham, Teagan P. Settelmeyer, Jody E. Hooper, Matthew N. Svalina, Yoshihiro Ishikawa, Keith Zientek, Zia Bajwa, Martin W. Goros, Brian S. Hernandez, Johannes E. Wolff, Michelle A. Rudek, Linping Xu, Nicole M. Anders, Ranadip Pal, Alexandria P. Harrold, Angela M. Davies, Arya Ashok & 18 others Darnell Bushby, Maria Mancini, Christopher Noakes, Neal C. Goodwin, Peter Ordentlich, James Keck, Douglas S. Hawkins, Erin R. Rudzinski, Bishwanath Chatterjee, Hans Peter Bächinger, Frederic G. Barr, Jennifer Liddle, Benjamin A. Garcia, Atiya Mansoor, Theodore J. Perkins, Christopher R. Vakoc, Joel E. Michalek, Charles Keller

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

Original languageEnglish (US)
Article numberaau7632
JournalScience Signaling
Volume11
Issue number557
DOIs
StatePublished - Nov 20 2018

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Oncogene Fusion
Rhabdomyosarcoma
Fusion reactions
Chemotherapy
Drug Therapy
Alveolar Rhabdomyosarcoma
Alveolar Epithelial Cells
Clinical Trials, Phase I
Histone Deacetylase Inhibitors
Chromatin Assembly and Disassembly
Gene Fusion
Radiotherapy
MicroRNAs
Sarcoma
Refractory materials
Chromatin
entinostat
Tumors
Cell Culture Techniques
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Bharathy, N., Berlow, N. E., Wang, E., Abraham, J., Settelmeyer, T. P., Hooper, J. E., ... Keller, C. (2018). The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Science Signaling, 11(557), [aau7632]. https://doi.org/10.1126/scisignal.aau7632

The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. / Bharathy, Narendra; Berlow, Noah E.; Wang, Eric; Abraham, Jinu; Settelmeyer, Teagan P.; Hooper, Jody E.; Svalina, Matthew N.; Ishikawa, Yoshihiro; Zientek, Keith; Bajwa, Zia; Goros, Martin W.; Hernandez, Brian S.; Wolff, Johannes E.; Rudek, Michelle A.; Xu, Linping; Anders, Nicole M.; Pal, Ranadip; Harrold, Alexandria P.; Davies, Angela M.; Ashok, Arya; Bushby, Darnell; Mancini, Maria; Noakes, Christopher; Goodwin, Neal C.; Ordentlich, Peter; Keck, James; Hawkins, Douglas S.; Rudzinski, Erin R.; Chatterjee, Bishwanath; Bächinger, Hans Peter; Barr, Frederic G.; Liddle, Jennifer; Garcia, Benjamin A.; Mansoor, Atiya; Perkins, Theodore J.; Vakoc, Christopher R.; Michalek, Joel E.; Keller, Charles.

In: Science Signaling, Vol. 11, No. 557, aau7632, 20.11.2018.

Research output: Contribution to journalArticle

Bharathy, N, Berlow, NE, Wang, E, Abraham, J, Settelmeyer, TP, Hooper, JE, Svalina, MN, Ishikawa, Y, Zientek, K, Bajwa, Z, Goros, MW, Hernandez, BS, Wolff, JE, Rudek, MA, Xu, L, Anders, NM, Pal, R, Harrold, AP, Davies, AM, Ashok, A, Bushby, D, Mancini, M, Noakes, C, Goodwin, NC, Ordentlich, P, Keck, J, Hawkins, DS, Rudzinski, ER, Chatterjee, B, Bächinger, HP, Barr, FG, Liddle, J, Garcia, BA, Mansoor, A, Perkins, TJ, Vakoc, CR, Michalek, JE & Keller, C 2018, 'The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma', Science Signaling, vol. 11, no. 557, aau7632. https://doi.org/10.1126/scisignal.aau7632
Bharathy N, Berlow NE, Wang E, Abraham J, Settelmeyer TP, Hooper JE et al. The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Science Signaling. 2018 Nov 20;11(557). aau7632. https://doi.org/10.1126/scisignal.aau7632
Bharathy, Narendra ; Berlow, Noah E. ; Wang, Eric ; Abraham, Jinu ; Settelmeyer, Teagan P. ; Hooper, Jody E. ; Svalina, Matthew N. ; Ishikawa, Yoshihiro ; Zientek, Keith ; Bajwa, Zia ; Goros, Martin W. ; Hernandez, Brian S. ; Wolff, Johannes E. ; Rudek, Michelle A. ; Xu, Linping ; Anders, Nicole M. ; Pal, Ranadip ; Harrold, Alexandria P. ; Davies, Angela M. ; Ashok, Arya ; Bushby, Darnell ; Mancini, Maria ; Noakes, Christopher ; Goodwin, Neal C. ; Ordentlich, Peter ; Keck, James ; Hawkins, Douglas S. ; Rudzinski, Erin R. ; Chatterjee, Bishwanath ; Bächinger, Hans Peter ; Barr, Frederic G. ; Liddle, Jennifer ; Garcia, Benjamin A. ; Mansoor, Atiya ; Perkins, Theodore J. ; Vakoc, Christopher R. ; Michalek, Joel E. ; Keller, Charles. / The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. In: Science Signaling. 2018 ; Vol. 11, No. 557.
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title = "The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma",
abstract = "Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45{\%} decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.",
author = "Narendra Bharathy and Berlow, {Noah E.} and Eric Wang and Jinu Abraham and Settelmeyer, {Teagan P.} and Hooper, {Jody E.} and Svalina, {Matthew N.} and Yoshihiro Ishikawa and Keith Zientek and Zia Bajwa and Goros, {Martin W.} and Hernandez, {Brian S.} and Wolff, {Johannes E.} and Rudek, {Michelle A.} and Linping Xu and Anders, {Nicole M.} and Ranadip Pal and Harrold, {Alexandria P.} and Davies, {Angela M.} and Arya Ashok and Darnell Bushby and Maria Mancini and Christopher Noakes and Goodwin, {Neal C.} and Peter Ordentlich and James Keck and Hawkins, {Douglas S.} and Rudzinski, {Erin R.} and Bishwanath Chatterjee and B{\"a}chinger, {Hans Peter} and Barr, {Frederic G.} and Jennifer Liddle and Garcia, {Benjamin A.} and Atiya Mansoor and Perkins, {Theodore J.} and Vakoc, {Christopher R.} and Michalek, {Joel E.} and Charles Keller",
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AU - Bharathy, Narendra

AU - Berlow, Noah E.

AU - Wang, Eric

AU - Abraham, Jinu

AU - Settelmeyer, Teagan P.

AU - Hooper, Jody E.

AU - Svalina, Matthew N.

AU - Ishikawa, Yoshihiro

AU - Zientek, Keith

AU - Bajwa, Zia

AU - Goros, Martin W.

AU - Hernandez, Brian S.

AU - Wolff, Johannes E.

AU - Rudek, Michelle A.

AU - Xu, Linping

AU - Anders, Nicole M.

AU - Pal, Ranadip

AU - Harrold, Alexandria P.

AU - Davies, Angela M.

AU - Ashok, Arya

AU - Bushby, Darnell

AU - Mancini, Maria

AU - Noakes, Christopher

AU - Goodwin, Neal C.

AU - Ordentlich, Peter

AU - Keck, James

AU - Hawkins, Douglas S.

AU - Rudzinski, Erin R.

AU - Chatterjee, Bishwanath

AU - Bächinger, Hans Peter

AU - Barr, Frederic G.

AU - Liddle, Jennifer

AU - Garcia, Benjamin A.

AU - Mansoor, Atiya

AU - Perkins, Theodore J.

AU - Vakoc, Christopher R.

AU - Michalek, Joel E.

AU - Keller, Charles

PY - 2018/11/20

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AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3-SMARCA4-miR-27a-PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.

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