Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

Abstract

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

Glucose Increases STAT3 Activation, Promoting Sustained XRCC1 Expression and Increasing DNA Repair

“…STAT3 activation following high glucose exposure has been documented in numerous cell lines [27,28]. We also found that STAT3 serves as an inducible regulator of XRCC1 in the non-tumorigenic human embryonic kidney cell lines HEK293T [3]. However, no links between increased glucose concentrations, the activation of STAT3, and increased XRCC1 and DNA repair have been made.…”

“…To examine the high glucose regulation of XRCC1, we exposed cells to 30 mM glucose for up to 24 h. We selected the osteosarcoma cell line U2OS, which has high STAT3 activation, and HEK293T, which we showed previously has an inducible STAT3 response [3]. HEK293T cells were grown in 25 mM glucose (basal glucose (BG)), and the U2OS cells were grown in 11 mM (BG).…”

“…We have identified dysregulation of DNA repair proteins in triple-negative breast cancer (TNBC) cells that alter the DNA repair capacity of these cells [1,2]. We also recently linked overexpression of X-ray cross-complementing group 1 (XRCC1), a base excision repair (BER) protein, to the transcriptional activities of signal transducer and activator of transcription 3 (STAT3) [3]. BER is essential to repairing the myriad of DNA base lesions accumulated from endogenous and exogenous exposures daily.…”

“…Our previous work demonstrated that STAT3 was a novel regulator of XRCC1 in TNBC cell lines, which have a constitutive activation of STAT3 [3,25]. STAT3 transcriptional activities are activated by phosphorylation at tyrosine 705 (Y705), leading to dimerization and translocation into the nucleus [26].…”

Связь Полиморфных Маркеров Генов ERCC2, ERCC5 И ABCB1 С Ответом На Лечение При Онкологических Заболеваниях На Фоне Беременности

“…Ответ на ХТ может быть обусловлен активностью систем репарации ДНК, в частности, системы эксцизионной репарации оснований (BER) или нуклеотидов (NER). Интегральным белком BER, координирующим сборку всего белкового комплекса репарации, является XRCC1, который кодируется геном XRCC1 [2]. Система репарации NER и изменения в ней, в частности, однонуклеотидные полиморфизмы, также играют важную роль в ответе на цитотоксическую терапию [3].…”