The RNA binding proteins LARP4A and LARP4B promote sarcoma and carcinoma growth and metastasis

Abstract

RNA-binding proteins (RBPs) are emerging as important regulators of pathogenesis, including cancer. Here we reveal that the recently characterised RBPs LARP4A and LARP4B are differentially overexpressed in primary osteosarcoma and osteosarcoma lung metastases, as well as in prostate cancer. Depletion of LARP4A and LARP4B inhibited primary tumour growth and metastatic spread in xenograft studies, as well as inhibiting cell proliferation, motility and migration. Transcriptomic profiling combined with high content multiparametric cell cycle analysis unveiled a central role for LARP4B, but not LARP4A, in regulating cell cycle progression in osteosarcoma and prostate cancer cell lines, potentially through modulating the post-transcriptional regulation of RNA targets that include key cell cycle proteins such as Cyclins B1 and E2, Aurora B and E2F1. Our work assigns new functions to LARP4A and LARP4B as pro-tumorigenic proteins in bone and prostate cancer, highlights their similarities while indicating distinct functional aspects, and adds significantly to the rapidly increasing roles of RBPs in different cancer models. Uncovering clear biological roles for these paralogous proteins provides new avenues for identifying novel tissue-specific targets and potential druggable intervention.

LARP4 is an RNA-binding protein that binds nuclear-encoded mitochondrial mRNAs to promote mitochondrial function

“…4 B). This is consistent with a recent study which showed that depletion of LARP4 in osteosarcoma cancer lines (MNNG/HOS; MG63) also reduced cell proliferation ( Coleman et al 2023b ). These data indicate that LARP4 is required for normal rates of proliferation in HEK293 cells and that LARP4 depletion is also associated with reduced proliferation rates in the osteosarcoma cancer cell line U2OS.…”

“…However, because mRNA abundance is a product of both stability and transcription rate, it remains a possibility that changes in the transcriptional rate of LARP4 target mRNAs could be masking the role of LARP4 in regulating target mRNA stability. Given that recruitment of LARP4 to the cytoplasmic surface of the mitochondria has been previously demonstrated ( Gabrovsek et al 2020 ; Coleman et al 2023b ) and we demonstrated that mitochondria-associated translation was reduced upon LARP4 depletion, LARP4 may play a direct role in the recruitment of a subset of its target mRNAs to the vicinity of the mitochondria to enhance their local translation and mitochondrial protein targeting. Additionally, both our proteomic analysis and immunofluorescence staining analysis of LARP4-depleted cells demonstrated nonmitochondrial accumulation of protein products encoded by mitochondrial RNA targets of LARP4, implicating LARP4 in the process of mitochondrial protein targeting.…”

“…In two recent studies, LARP4 was found to colocalize with TOM20 at mitochondria in HEK293 cells as well as in the MG63 and PC3 cancer cell lines ( Gabrovsek et al 2020 ; Coleman et al 2023b ). In HEK293 cells the recruitment of LARP4 to the surface of mitochondria was shown to be mediated by the protein kinase A adaptor protein AKAP1, where LARP4 acts as a general translation factor to promote the local translation of AKAP1-associated mRNAs ( Gabrovsek et al 2020 ).…”

“…Later studies demonstrated that LARP4 plays a functional role in maintaining poly(A) tail (PAT) length, likely through competition with deadenylases for PABP binding sites (Mattijssen et al 2017(Mattijssen et al , 2020. Recently, LARP4 was found to colocalize with TOM20 at mitochondria as well as cofractionate with mitochondria in the MG63 and PC3 cancer cell lines (Coleman et al 2023b). Additionally, LARP4 was reported to be recruited to the mitochondrial surface in HEK293 cells through an interaction with the PKA adaptor protein AKAP1, which also functions as an RBP (Gabrovsek et al 2020).…”