Chemotherapy suppresses SHH gene expression via a specific enhancer

Sonic hedgehog (SHH) signaling triggers an evolutionarily conserved pathway that is crucial for the development and regeneration of a wide range of organs (Briscoe and Thérond, 2013; Petrova and Joyner, 2014; Sasai et al., 2019). Two important concepts are emerging from early investigations: SHH is a major mitogen in organ development, particularly the gastrointestinal (GI) tract (Mao et al., 2010; Huycke et al., 2019); and SHH expression is under the control of long-range enhancers (Anderson and Hill, 2014; Anderson et al., 2014; Amano, 2020). The regulation of SHH gene expression is a classical model of long-range enhancer function: various enhancers spanning the 1MB upstream regulatory region control its tissue-specific expression (Sagai et al., 2009; Tsukiji et al., 2014; Anderson and Hill, 2014; Anderson et al., 2014; Amano, 2020). However, the transcription factors that mediate these regulatory mechanisms remain largely unclear.

SHH is ubiquitously expressed in the embryonic gut epithelium and controls its development (Mao et al., 2010; Huycke et al., 2019; Roberts et al., 1995; Madison et al., 2005; Shyer et al., 2015). In adult gut, SHH expression is reduced, although it is still required for stem cell maintenance and tissue homeostasis (Coquenlorge et al., 2019; Baulies et al., 2020; Zhu et al., 2021). SHH signaling is involved in the progression of GI cancers (Mazumdar et al., 2011; Xu et al., 2012; Regan et al., 2017), which are a major threat to human health. We previously showed that chemotherapy down-regulates SHH expression in feather and hair follicles, resulting in tissue damage as an adverse effect (Xie et al., 2015; Gao et al., 2019; Haslam et al., 2021). It remains unclear whether chemotherapy targets SHH gene expression in cancer and, if so, what transcription factors and enhancers are involved.

Using GI cancers as a model, we report that the SHH gene is directly downstream of immediate early genes (IEGs) and particularly EGR1. A specific 139 Kb upstream enhancer is targeted by chemotherapy, which then suppresses SHH gene expression. Our results defined the regulatory role of IEGs in SHH expression and identified a chemo-responsive enhancer for classical chemotherapy drugs such as 5-fluorouracil (5FU), which is widely used to treat GI cancers.

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