NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness

0Citations
Citations of this article
5Readers
Mendeley users who have this article in their library.

This article is free to access.

Abstract

Mutations in APC, found in 80% of colon caner, enhance β-catenin stabilization, which is the initial step of colonic tumorigenesis. However, the core transcriptional mechanism underlying the induction of colon cancer stemness by stable β-catenin remains unclear. Here, we found that inducible inhibition of β-catenin suppressed elongation of Pol II and RNA polymerase-associated factor 1 complex (PAF1C) around the transcription start site (TSS) of LGR5. Moreover, stable β-catenin enhanced the formation of active Pol II complex cooperatively with CDC73 and CDK9 by facilitating the recruitment of DRB sensitivity-inducing factor (DSIF) and negative elongation factor (NELF) complexes to the Pol II complex. Subsequently, stable β-catenin facilitated the formation of the Pol II–DSIF–PAF1C complex, suggesting that stable β-catenin induces cancer stemness by stimulating active Pol II complex through NELF and PAF1C. Furthermore, NELF or PAF1C inhibition recapitulated the changes in cancer stemness-related gene expression induced by the inhibition of stable β-catenin and suppressed colon cancer stemness. Additionally, the chemical inhibition of CDK12 (a downstream transcription CDK of PAF1C) suppressed colon cancer stemness. These results suggest that NELF and PAF1C are the core transcriptional machineries that control expression of colon cancer stemness-inducing genes and may be therapeutic targets for colon cancer.

Cite

CITATION STYLE

APA

Aoki, K., Nitta, A., & Igarashi, A. (2024). NELF and PAF1C complexes are core transcriptional machineries controlling colon cancer stemness. Oncogene, 43(8), 566–577. https://doi.org/10.1038/s41388-023-02930-0

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free