RNA-binding proteins (RBPs) are increasingly identified
as post-transcriptional drivers of cancer progression.
The RBP LARP1 is an mRNA stability regulator,
and elevated expression of the protein in hepatocellular
and lung cancers is correlated with adverse
prognosis. LARP1 associates with an mRNA interactome
that is enriched for oncogenic transcripts.
Here we explore the role of LARP1 in epithelial ovarian
cancer, a disease characterized by the rapid acquisition
of resistance to chemotherapy through the
induction of pro-survival signalling. We show, using
ovarian cell lines and xenografts, that LARP1 is required
for cancer cell survival and chemotherapy resistance.
LARP1 promotes tumour formation in vivo
and maintains cancer stem cell-like populations. Using
transcriptomic analysis following LARP1 knockdown,
cross-referenced against the LARP1 interactome,
we identify BCL2 and BIK as LARP1 mRNA
targets. We demonstrate that, through an interaction
with the 3 untranslated regions (3 UTRs) of BCL2
and BIK, LARP1 stabilizes BCL2 but destabilizes BIK
with the net effect of resisting apoptosis. Together,
our data indicate that by differentially regulating the
stability of a selection of mRNAs, LARP1 promotes
ovarian cancer progression and chemotherapy resistance.