Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis

Maria Angeles Lillo Osuna, Jesus Garcia-Lopez, Ikbale El Ayachi, Iram Fatima, Aysha B. Khalid, Jerusha Kumpati, Alexandria V. Slayden, Tiffany Seagroves, Gustavo Miranda-Carboni, Susan Miranda

Research output: Contribution to journalArticle

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Abstract

Osteosarcoma is a malignant tumor in the bone, which originates from normal osteoblasts or osteoblast precursors. Normal osteoblasts express estrogen receptor alpha (ERa); however, osteosarcomas do not express ERa due to promoter DNA methylation. Here we show that treatment of 143B osteosarcoma cells with decitabine (DAC, 5-Aza-2 0 -deoxycytidine) induces expression of ERa and leads to decreased proliferation and concurrent induction of osteoblast differentiation. DAC exposure reduced protein expression of metastasis-associated markers VIMENTIN, SLUG, ZEB1, and MMP9, with a concurrent decrease in mRNA expression of known stem cell markers SOX2, OCT4, and NANOG. Treatment with 17b-estradiol (E2) synergized with DAC to reduce proliferation. Overexpression of ERa inhibited proliferation and induced osteoblast differentiation, whereas knockout of ERa by CRISPR/Cas9 prevented the effects of DAC. In an orthotopic model of osteosarcoma, DAC inhibited tumor growth and metastasis of 143B cells injected into the tibia of NOD SCID gamma mice. Furthermore, ERa overexpression reduced tumor growth and metastasis, and ERa knockout prevented the effects of DAC in vivo. Together, these experiments provide preclinical evidence that the FDA-approved DNA methylation inhibitor DAC may be repurposed to treat patients with osteosarcoma based on its efficacy to decrease proliferation, to induce osteoblast differentiation, and to reduce metastasis to visceral organs. Significance: These findings describe the effects of DNA methyltransferase inhibition on ERa and its potential role as a tumor suppressor in osteosarcoma.

Original languageEnglish (US)
Pages (from-to)1054-1068
Number of pages15
JournalCancer Research
Volume79
Issue number6
DOIs
StatePublished - Jan 1 2019

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decitabine
Estrogen Receptor alpha
Osteosarcoma
Osteoblasts
Neoplasm Metastasis
Growth
DNA Methylation
Neoplasms
Clustered Regularly Interspaced Short Palindromic Repeats
Inbred NOD Mouse
SCID Mice
Methyltransferases
Tibia

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Osuna, M. A. L., Garcia-Lopez, J., Ayachi, I. E., Fatima, I., Khalid, A. B., Kumpati, J., ... Miranda, S. (2019). Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. Cancer Research, 79(6), 1054-1068. https://doi.org/10.1158/0008-5472.CAN-18-1255

Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. / Osuna, Maria Angeles Lillo; Garcia-Lopez, Jesus; Ayachi, Ikbale El; Fatima, Iram; Khalid, Aysha B.; Kumpati, Jerusha; Slayden, Alexandria V.; Seagroves, Tiffany; Miranda-Carboni, Gustavo; Miranda, Susan.

In: Cancer Research, Vol. 79, No. 6, 01.01.2019, p. 1054-1068.

Research output: Contribution to journalArticle

Osuna MAL, Garcia-Lopez J, Ayachi IE, Fatima I, Khalid AB, Kumpati J et al. Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. Cancer Research. 2019 Jan 1;79(6):1054-1068. https://doi.org/10.1158/0008-5472.CAN-18-1255
Osuna, Maria Angeles Lillo ; Garcia-Lopez, Jesus ; Ayachi, Ikbale El ; Fatima, Iram ; Khalid, Aysha B. ; Kumpati, Jerusha ; Slayden, Alexandria V. ; Seagroves, Tiffany ; Miranda-Carboni, Gustavo ; Miranda, Susan. / Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. In: Cancer Research. 2019 ; Vol. 79, No. 6. pp. 1054-1068.
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