Identification of tRNA‐derived small RNA (tsRNA) responsive to the tumor suppressor, RUNX1, in breast cancer

Abstract

Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)‐derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt‐related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts‐19, ts‐29, ts‐46, and ts‐112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts‐112 and RUNX1 anticorrelate in normal‐like mammary epithelial and breast cancer lines is consistent with tumor‐related activity of ts‐112 and tumor suppressor activity of RUNX1. Inhibition of ts‐112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts‐112 mimic in normal‐like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts‐112. Moreover, RUNX1 may repress ts‐112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.

Transfer RNA-Derived Small RNAs: Another Layer of Gene Regulation and Novel Targets for Disease Therapeutics

“…57 The regulation of type II tsRNA biogenesis has only recently started to be revealed. Farina et al 58 determined that four type II tsRNAs (ts-19, ts-29, ts-46, and ts-112) expression levels were responsive to the RUNX1 tumor suppressor expression and that ts-112 was inversely correlated with RUNX1 and possessed oncogenic activity. This finding suggests that expression of some type II tsRNAs might be regulated by tumor-suppressor genes or oncogenes, which could also explain differential expression of tsRNAs in cancer cells.…”

Action mechanisms and research methods of tRNA-derived small RNAs

“…71 Researchers have found that runt-related transcription factor 1 (RUNX1) may prevent the excessive malignant proliferation of breast cancer epithelial cells by inhibiting the carcinogenesis of ts-112, thereby enhancing its role in maintaining the healthy function of breast epithelial cells. 72 Researchers have used RNA-seq to analyze the expression levels of tRF in normal prostate tissues adjacent to prostate cancer tissues and with cells from tissues at different stages of prostate cancer, and found 598 differentially expressed tRFs. 73 In recurrent prostate cancer, the tRF from tRNA Phe-GAA was significantly downregulated compared with that of the adjacent normal tissue, while the tRF from tRNA Lys-CTT was upregulated and expressed at higher levels in higher grade prostate cancer, and the patients with highly expressed tRF based on tRNA Lys-CTT /tRNA Phe-GAA had shorter survival and recurrence periods.…”

tRNA-derived RNA fragments in cancer: current status and future perspectives

“…Similarly, 5′-SHOT-RNA can also enhance cell proliferation in BC cells [66]. Inhibition of ts-112, the expression of which is regulated by the tumor suppressor runt-related transcription factor 1 (RUNX1), can reduce the proliferative capacity of aggressive breast cancer cells while its overexpression promotes cell growth in normal-like mammary epithelial cells [67].…”