Chemotherapy suppresses <i>SHH</i> gene expression via a specific enhancer

Yafei Zhang; Jianqiong Lin; Kaibin Yang; Zhicao Yue

doi:10.1016/j.jgg.2022.08.002

Volume 50 Issue 1

Jan. 2023

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Chemotherapy suppresses SHH gene expression via a specific enhancer

doi: 10.1016/j.jgg.2022.08.002

Department of Cell Biology and Medical Genetics, International Cancer Center, and Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen University Medical School, Shenzhen, Guangdong 518060, China

Funds:

We thank Mr. Qingxiang Gao, and Ms. Qiaoxue Zhao for technical help. This work is supported by the National Natural Science Foundation of China (31871468) and a stable supporting program from the Shenzhen Science and Technology Innovation Commission (20200808172413001) to ZY.

Received Date: 2021-12-06
Accepted Date: 2022-08-16
Rev Recd Date: 2022-08-12
Publish Date: 2023-01-28

Abstract

Abstract

Sonic hedgehog (SHH) signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal (GI) cancer progression. Regulation of SHH gene expression is a paradigm of long-range enhancer function. Using the classical chemotherapy drug 5-fluorouracil (5FU) as an example, here we show that SHH gene expression is suppressed by chemotherapy. SHH is 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 EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy. We further demonstrate that down-regulation of SHH expression 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 SHH is a stress-responsive gene downstream of IEGs, and that traditional chemotherapy targets a specific enhancer to suppress its expression.
- Sonic hedgehog,
- Chemotherapy,
- Immediate early genes,
- EGR1,
- 5-Fluorouracil

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References

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