An epigenetic screening determines BET proteins as targets to suppress self-renewal and tumorigenicity in canine mammary cancer cells

Author(s)

Xavier, Pedro L. P. ^[1] ; Cordeiro, Yonara G. ^[1] ; Alexandre, Pamela A. ^{[1, 2]} ; Pires, Pedro R. L. ^[1] ; Saranholi, Bruno H. ^[3] ; Silva, Edson R. ^[4] ; Mueller, Susanne ^[5] ; Fukumasu, Heidge ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Anim Sci & Food Engn, Dept Vet Med, Lab Comparat & Translat Oncol LOCT, Pirassununga - Brazil

^[2] CSIRO Agr & Food, Commonwealth Sci & Ind Res Org, Brisbane, Qld - Australia

^[3] Univ Fed Sao Carlos, Dept Genet & Evolut, Sao Carlos, SP - Brazil

^[4] Univ Sao Paulo, Fac Anim Sci & Food Engn, Dept Vet Med, Pirassununga - Brazil

^[5] Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, Struct Genom Consortium, Frankfurt - Germany

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 9, NOV 22 2019.
• Web of Science Citations: 0

Abstract

Targeting self-renewal and tumorigenicity has been proposed as a potential strategy against cancer stem cells (CSCs). Epigenetic proteins are key modulators of gene expression and cancer development contributing to regulation and maintenance of self-renewal and tumorigenicity. Here, we have screened a small-molecule epigenetic inhibitor library using 3D in vitro models in order to determine potential epigenetic targets associated with self-renewal and tumorigenicity in Canine Mammary Cancer (CMC) cells. We identified inhibition of BET proteins as a promising strategy to inhibit CMC colonies and tumorspheres formation. Low doses of (+)-JQ1 were able to downregulate important genes associated to self-renewal pathways such as WNT, NOTCH, Hedgehog, PI3K/AKT/mTOR, EGF receptor and FGF receptor in CMC tumorspheres. In addition, we observed downregulation of ZEB2, a transcription factor important for the maintenance of self-renewal in canine mammary cancer cells. Furthermore, low doses of (+)-JQ1 were not cytotoxic in CMC cells cultured in 2D in vitro models but induced G2/M cell cycle arrest accompanied by upregulation of G2/M checkpoint-associated genes including BTG2 and CCNG2. Our work indicates the BET inhibition as a new strategy for canine mammary cancers by modulating the self-renewal phenotype in tumorigenic cells such as CSCs. (AU)

• FAPESP's process: 17/11966-4 - Epigenetic modulations and self-renewal potential of canine mammary cancer cells: the search for potential therapeutic targets
• Grantee: Pedro Luiz Porfirio Xavier
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/05778-6 - Combined inhibition of BET proteins AND HDACs as an effective strategy for the treatment of mammary cancer: a comparative study
• Grantee: Pedro Luiz Porfirio Xavier
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/02493-7 - Mammary tumors of dogs and the cancer stem cell theory: a comparative and translational approach
• Grantee: Heidge Fukumasu
• Support Opportunities: Research Grants - Young Investigators Grants