Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity

Lydia Hepburn, Angela McHugh, Kenneth Fernandes, Garry Boag, Charlotte Proby, Irene Leigh, Mark Saville

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
152 Downloads (Pure)

Abstract

We show that suppression of the spliceosome has potential for the treatment of cutaneous squamous cell carcinoma (cSCC). The small-molecule inhibitors of the spliceosome at the most advanced stage of development target the splicing factor SF3B1/SF3b155. The majority of cSCC cell lines are more sensitive than normal skin cells to death induced by the SF3B1 inhibitor pladienolide B. Knockdown of SF3B1 and a range of other splicing factors with diverse roles in the spliceosome can also selectively kill cSCC cells. We demonstrate that endogenous c-MYC participates in conferring sensitivity to spliceosome inhibition. c-MYC expression is elevated in cSCC lines and its knockdown reduces alterations in mRNA splicing and attenuates cell death caused by interference with the spliceosome. In addition, this study provides further support for a key role of the p53 pathway in the response to spliceosome disruption. SF3B1 inhibition causes wild-type p53 upregulation associated with altered mRNA splicing and reduced protein expression of both principal p53 negative regulators MDMX/MDM4 and MDM2. We observed that wild-type p53 can promote pladienolide B-induced death in tumour cells. However, p53 is commonly inactivated by mutation in cSCCs and p53 participates in killing normal skin cells at high concentrations of pladienolide B. This may limit the therapeutic window of SF3B1 inhibitors for cSCC. We provide evidence that, while suppression of SF3B1 has promise for treating cSCCs with mutant p53, inhibitors which target the spliceosome through SF3B1-independent mechanisms could have greater cSCC selectivity as a consequence of reduced p53 upregulation in normal cells.
Original languageEnglish
Pages (from-to)23029-23046
Number of pages18
JournalOncotarget
Volume9
Issue number33
DOIs
Publication statusPublished - 1 May 2018

Keywords

  • squamous cell carcinoma
  • spliceosome
  • c-MYC
  • p53
  • MDM2

Fingerprint Dive into the research topics of 'Targeting the spliceosome for cutaneous squamous cell carcinoma therapy: a role for c-MYC and wild-type p53 in determining the degree of tumour selectivity'. Together they form a unique fingerprint.

Cite this