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Published on: July 20, 2019
INI1 induces interferon signaling and spindle checkpoint in rhabdoid tumors
Alexei Morozov1, Seung Jae Lee, Zhi-Kai Zhang
1Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Purpose:
Rhabdoid tumors are rare but aggressive pediatric malignancies characterized by biallelic loss of INI1/hSNF5. Reintroduction of INI1 causes cell arrest and senescence in rhabdoid cells. Our purpose was to identify INI1-downstream genes and to determine their functional and therapeutic significance for rhabdoid tumors.
Experimental Design:
INI1 downstream targets in rhabdoid cells were identified using a cDNA microarray analysis and the expression of selected INI1 targets was confirmed by quantitative reverse transcription-PCR, Western analysis, and/or immunohistochemical analysis of rhabdoid cells and primary rhabdoid tumors. To determine the functional significance of downstream targets, activated targets of INI1 were induced and repressed targets of INI1 were knocked down (by using RNA interference) in rhabdoid cells, in the absence of INI1. Consequence of altered expression of INI1 downstream targets for rhabdoid cell survival, cell cycle, and apoptosis was assessed.
Results:
Microarray studies indicated that INI1 activated IFN-stimulated genes at early time points and senescence markers at late time points and repressed mitotic genes such as Polo like kinase 1 (PLK1), selectively in rhabdoid cells. Treatment of rhabdoid cells with recombinant IFNs resulted in induction of IFN-stimulated genes, G1 arrest, and flat cell formation. PLK1 was overexpressed in primary human and mouse rhabdoid tumors. RNA interference-mediated knock down of PLK1 in rhabdoid cells resulted in mitotic arrest, aberrant nuclear division, decreased survival, and induction of apoptosis.
Conclusions:
Targeting downstream effectors of INI1 such as IFN pathway and mitotic genes leads to antiproliferative effects in rhabdoid cells. IFN treatment and down-modulation of PLK1 constitute potential novel therapeutic strategies for rhabdoid tumors.
Insights
Targeting INI1 downstream genes, like interferon-stimulated genes and Polo-like kinase 1 (PLK1), shows promise for treating aggressive pediatric rhabdoid tumors. Modulating these targets can inhibit tumor cell growth and induce apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Pediatric Malignancies
Background:
- Rhabdoid tumors are aggressive pediatric cancers often linked to INI1/hSNF5 loss.
- INI1 reintroduction induces cell cycle arrest and senescence in rhabdoid tumor cells.
Purpose of the Study:
- Identify INI1-downstream genes in rhabdoid tumors.
- Determine the functional and therapeutic significance of these downstream targets.
Main Methods:
- cDNA microarray analysis to identify INI1 targets.
- Quantitative RT-PCR, Western analysis, and immunohistochemistry for validation.
- RNA interference to assess the impact of target modulation on cell survival, cell cycle, and apoptosis.
Main Results:
- INI1 activates interferon-stimulated genes and senescence markers, while repressing mitotic genes like PLK1.
- IFN treatment induced G1 arrest and flat cell formation in rhabdoid cells.
- PLK1 knockdown led to mitotic arrest, decreased survival, and apoptosis; PLK1 was overexpressed in rhabdoid tumors.
Conclusions:
- Targeting INI1 downstream effectors, including the IFN pathway and mitotic genes, yields antiproliferative effects.
- IFN treatment and PLK1 downregulation represent potential therapeutic strategies for rhabdoid tumors.
