# FBXW7 Targets the SPT6‐ΔNp63 Axis for Degradation to Inhibit Esophageal Tumorigenesis Induced by 4‐Nitroquinoline N‐Oxide

## TL;DR

FBXW7 prevents esophageal cancer by breaking down SPT6 and ΔNp63, and high SPT6 levels with low FBXW7 are linked to worse patient outcomes.

## Contribution

FBXW7 is shown to inhibit esophageal tumorigenesis by targeting the SPT6-ΔNp63 axis for degradation.

## Key findings

- FBXW7 inhibits 4NQO-induced esophageal tumorigenesis but not Pik3CaE545K-induced tumorigenesis.
- FBXW7 promotes degradation of SPT6 and ΔNp63, which are pro-proliferative in ESCC cells.
- High SPT6 and low FBXW7 levels in ESCC tissues correlate with poorer patient survival.

## Abstract

FBXW7 (F‐box and WD repeat domain‐containing 7) is a classic tumor suppressor that promotes ubiquitylation and degradation of various oncoproteins. Although its tumor suppressor role in many types of cancers has been established, whether and how FBXW7 regulates in vivo esophageal tumorigenesis was previously unknown. Here, we report, using genetically modified mouse models, that Fbxw7 inhibits esophageal tumorigenesis induced by the carcinogen 4NQO (4‐nitroquinoline N‐oxide), but not by Pik3CaE545K (phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha), a frequently mutated gene in human esophageal squamous cell carcinoma (ESCC). Mechanistically, FBXW7 depletion causes the accumulation of SPT6 (suppressor of Ty6), a transcriptional elongation factor, which is a novel substrate of FBXW7. SPT6 acts as a transcriptional co‐activator of ΔNp63, which is also a substrate of FBXW7 in ESCC cells. Both SPT6 and ΔNp63, accumulated upon FBXW7 knockdown, contribute to the proliferation of ESCC cells. In clinical human ESCC tissues, the protein levels of SPT6 and FBXW7 are inversely correlated, and high SPT6 levels with low FBXW7 levels predict poorer patient survival. Collectively, FBXW7 acts as a tumor suppressor in ESCC by promoting the degradation of both SPT6 and ΔNp63, and the SPT6‐ΔNp63 axis may serve as a therapeutic target for ESCC.

In normal cells, FBXW7 promotes ubiquitylation and degradation of SPT6 and ΔNp63 to keep their pro‐proliferative functions under control. During esophageal tumorigenesis, FBXW7 is inactivated by mutations or deletion, leading to the accumulation of SPT6 and ΔNp63, with ΔNp63 also being up‐regulated by SPT6. Together with 4NQO‐induced initiation, Fbxw7 deletion‐mediated activation of the SPT6‐ΔNp63 axis promotes ESCC development.