MicroRNA-like snoRNA-Derived RNAs (sdRNAs) Promote Castration-Resistant Prostate Cancer

Abstract

We have identified 38 specifically excised, differentially expressed snoRNA fragments (sdRNAs) in TCGA prostate cancer (PCa) patient samples as compared to normal prostate controls. SnoRNA-derived fragments sdRNA-D19b and -A24 emerged among the most differentially expressed and were selected for further experimentation. We found that the overexpression of either sdRNA significantly increased PC3 (a well-established model of castration-resistant prostate cancer (CRPC)) cell proliferation, and that sdRNA-D19b overexpression also markedly increased the rate of PC3 cell migration. In addition, both sdRNAs provided drug-specific resistances with sdRNA-D19b levels correlating with paclitaxel resistance and sdRNA-24A conferring dasatinib resistance. In silico and in vitro analyses revealed that two established PCa tumor suppressor genes, CD44 and CDK12, represent targets for sdRNA-D19b and sdRNA-A24, respectively. This outlines a biologically coherent mechanism by which sdRNAs downregulate tumor suppressors in AR-PCa to enhance proliferative and metastatic capabilities and to encourage chemotherapeutic resistance. Aggressive proliferation, rampant metastasis, and recalcitrance to chemotherapy are core characteristics of CRPC that synergize to produce a pathology that ranks second in cancer-related deaths for men. This study defines sdRNA-D19b and -A24 as contributors to AR-PCa, potentially providing novel biomarkers and therapeutic targets of use in PCa clinical intervention.

snoRNAs in hematopoiesis and blood malignancies: A comprehensive review

“…The TCGA database shows that there is deregulation of 38 specific sdRNAs in prostate cancer. The sdRNAs, D19 and A24, downregulate the tumor suppressor genes and promote proliferation, metastasis, and chemoresistance (Coley et al, 2022). The functions of snoRNAs are depicted in Figure 2.…”

Small Nucleolar Derived RNAs as Regulators of Human Cancer

“…A study published in 2022 by our lab identified 38 specifically-excised and differentially-expressed sdRNAs in prostate cancer [ 73 ]. We began by querying PCa patient TCGA datasets alongside TCGA-normal prostate using an in-house web-based search algorithm SURFR (Short Uncharacterized RNA Fragment Recognition).…”

“…Further, five of these were significantly overexpressed in MDA-MB-237 compared to MCF7 breast cancer [ 72 ]. Most recently, in 2022, our lab similarly described 38 unique sdRNAs differentially expressed in prostate cancer patient samples [ 73 ] ( Table 2 ).…”

“…( D ) sdRNA excised from SNORD93 (ENSG00000221740) was found to function as a tumor-promoting RNA and is upregulated in breast cancer [ 72 ]. ( E ) sdRNA produced from SNORA24 (ENSG00000275994) was functionally identified as a tumor-promoting RNA and is upregulated in prostate cancer [ 73 ]. ( F ) sdRNA derived from SNORD19B (ENSG00000238862) was determined to function as a tumor-promoting RNA and is upregulated in prostate cancer [ 73 ].…”

Small Nucleolar RNAs and Their Comprehensive Biological Functions in Hepatocellular Carcinoma

“…SnoRNAs can also act as the downstream molecule of p53 and MYC responsible for tumorigenesis [ 28 , 29 ]. Furthermore, a large group of sdRNAs is significantly associated with the characteristics of the tumor-immune microenvironment, and some of the sdRNAs function similar to the microRNAs involved in cancer progression and chemoresistance [ 30 , 31 ].…”