CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide

Oct 17, 2017Neuro-oncology

CUX1 boosts DNA repair activity and helps brain cancer cells resist the drug temozolomide

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

CUX1 protein expression is high in most glioblastomas and affects treatment resistance.

CUT domains are shown to stimulate the activity of the DNA repair protein APE1.
Knockdown of CUX1 increases the number of DNA damage sites and decreases APE1 activity.
Overexpression of CUX1 enhances APE1 activity and reduces DNA damage sites.
CUX1 knockdown decreases glioblastoma cell resistance to temozolomide and combined treatment with ionizing radiation.
Conversely, CUX1 overexpression or a short active protein with two CUT domains increases resistance to these treatments.

AI simplified

BACKGROUND: Cut Like homeobox 1 (CUX1), which encodes an auxiliary factor in base excision repair, resides on 7q22.1, the most frequently and highly amplified chromosomal region in glioblastomas. The resistance of glioblastoma cells to the mono-alkylating agent temozolomide is determined to some extent by the activity of apurinic/apyrimidinic endonuclease 1 (APE1).

METHODS: To monitor the effect of CUX1 and its CUT domains on APE1 activity, DNA repair assays were performed with purified proteins and cell extracts. CUX1 protein expression was analyzed by immunohistochemistry using a tumor microarray of 150 glioblastoma samples. The effect of CUX1 knockdown and overexpression on the resistance of glioblastoma cell lines to temozolomide was investigated.

RESULTS: We show that CUT domains stimulate APE1 activity. In agreement with these findings, CUX1 knockdown causes an increase in the number of abasic sites in genomic DNA and a decrease in APE1 activity as measured in cell extracts. Conversely, ectopic CUX1 expression increases APE1 activity and lowers the number of abasic sites. Having established that CUX1 is expressed at high levels in most glioblastomas, we next show that the resistance of glioblastoma cells to temozolomide and to a combined treatment of temozolomide and ionizing radiation is reduced following CUX1 knockdown, but increased by overexpression of CUX1 or a short protein containing only 2 CUT domains, which is active in DNA repair but devoid of transcriptional activity.

CONCLUSION: These findings indicate that CUX1 expression level impacts on the response of glioblastoma cells to treatment and identifies the CUT domains as potential therapeutic targets.

Full Text

Full text is available at the source.

View full text ↗

CUX1 stimulates APE1 enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief