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  • Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple-negative breast cancer.

Potentiation of cancerous progression by LISCH7 via direct stimulation of TGFB1 transcription in triple-negative breast cancer.

Journal of cellular biochemistry (2020-02-13)
Xiaojiang Tang, Yuhui Zhou, Yang Liu, Wei Zhang, Chao Liu, Changyou Yan
ABSTRACT

As an aggressive breast cancer (BCa) subtype, triple-negative breast cancer (TNBC) responses poorly to chemotherapy and endocrine therapy, and usually has a worse prognosis. This is largely due to the lack of specific therapeutic targets, laying claim to an imperious demand to clarify the key signaling pathways potentiating TNBC progression. Herein, we report that expression levels of the liver-specific bHLH-Zip transcription factor (LISCH7), a recently identified key player in cancerous progression, preferentially enriched in TNBC in comparison with other BCa subtypes, and this upregulation was observed to be correlated to a poor survival outcome in patients with TNBC. Ablation of LISCH7 in TNBC cells impaired cell proliferation, reduced cell invasiveness, and enhanced sensitivity to the first-line chemotherapeutic drug docetaxel at both in vitro and in vivo levels. Importantly, concurrent induction of TGFB1, the gene encoding transforming growth factor-β1 (TGF-β1), an essential multipluripotent regulator of TNBC, was accompanied with these alterations in cancerous properties. We further showed that LISCH7 could directly bind to the TGFB1 promoter and stimulate TGFB1 transcription in TNBC cells. The recruitment of LISCH7 onto the TGFB1 chromatin and transactivation of TGFB1 were substantially augmented by treatment with the exogenous TGF-β1 in a time- and dose-dependent manner. Collectively, these findings suggest that LISCH7 and TGF-β1 form a reciprocal positive regulatory loop and cooperatively regulate cancerous progression in TNBC cells. Thus, simultaneous inhibition of both LISCH7 and TGF-β1 signaling may represent a more effective approach to counteract advanced TNBC.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MISSION® esiRNA, targeting human SMAD4
Sigma-Aldrich
21-Hydroxyprogesterone, ≥97% (HPLC)