Chemotherapy suppresses SHHgene expression via a specific enhancer

Autor: Zhang, Yafei, Lin, Jianqiong, Yang, Kaibin, Yue, Zhicao
Zdroj: Journal of Genetics and Genomics; January 2023, Vol. 50 Issue: 1 p27-37, 11p
Abstrakt: Sonic hedgehog (SHH) signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal (GI) cancer progression. Regulation of SHHgene expression is a paradigm of long-range enhancer function. Using the classical chemotherapy drug 5-fluorouracil (5FU) as an example, here we show that SHHgene expression is suppressed by chemotherapy. SHHis downstream of immediate early genes (IEGs), including Early growth response 1 (Egr1). A specific 139 kb upstream enhancer is responsible for its down-regulation. Knocking down EGR1expression or blocking its binding to this enhancer renders SHHunresponsive to chemotherapy. We further demonstrate that down-regulation of SHHexpression does not depend on 5FU's impact on nucleotide metabolism or DNA damage; rather, a sustained oxidative stress response mediates this rapid suppression. This enhancer is present in a wide range of tumors and normal tissues, thus providing a target for cancer chemotherapy and its adverse effects on normal tissues. We propose that SHHis a stress-responsive gene downstream of IEGs, and that traditional chemotherapy targets a specific enhancer to suppress its expression.
Databáze: Supplemental Index