Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner

Abstract

The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

Hedgehog Signaling: From Basic Biology to Cancer Therapy

“…These studies focused on the active forms of GLI. A recent report suggested context-dependent arsenic attenuation of both GLI activator and repressor forms (Li et al, 2016). Pan inhibition may explain why arsenic can be carcinogenic where GLI repressor plays a dominant role (Fei et al, 2010).…”

Hedgehog-GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells

“…On the other hand, GLI1 has been shown to be a target of arsenic trioxide (ATO), which is FDA approved for the therapy of adult patients with acute promyelocytic leukaemia (APL) 38 . A phase I trial investigating the co-administration of ATO and 5-Fluorouracil/Leucovorin in patients with advanced/relapsed colorectal cancer showed that ATO was well tolerated and that in some patients it was associated with down-regulated thymidylate synthase expression, indicating a therapeutic response, and increased survival 39 ; a later study investigated GLI1 levels in biopsies from the said clinical trial and found that it resulted to be down modulated after ATO administration 40 .…”

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals

“…Recently, our laboratory found that subacute arsenic treatment in SKH‐1 hairless mice disrupts the Hippo signaling pathway, leading to the disruption of tight/adherens junctions . Yap nuclear translocation and transcription of Yap target genes, including Gli2 , which encodes an important transcription factor in Sonic hedgehog signaling, are considered important in various delayed cutaneous manifestations, including the skin cancers …”

“…47 Yap nuclear translocation and transcription of Yap target genes, including Gli2, which encodes an important transcription factor in Sonic hedgehog signaling, are considered important in various delayed cutaneous manifestations, including the skin cancers. 54,55 Arsine gas Arsine is a colorless, non-irritating gas with a garliclike order at concentrations of 0.5 ppm or above. 56 It is the most toxic form of inorganic arsenic, and the inhalation of small amounts may be fatal.…”