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Targeting the splicing factor hnRNP M with an endogenous circular RNA aptamer suppresses cancer metastasis [shhnRNPM]

ABSTRACT: Alternative splicing (AS) is a key regulatory mechanism that expands transcriptomic diversity and is frequently hijacked by cancer cells to drive epithelial-mesenchymal transition (EMT), thereby promoting invasion and therapy resistance. However, therapeutic strategies to reprogram pathological AS networks remain limited. Here, we identified a circular RNA, MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ), that functions as an endogenous aptamer targeting the splicing factor hnRNP M, a central regulator of EMT-related AS reprogramming. As an endogenous repressor of hnRNP M, MASCOT maintains the epithelial status of cancer cells and suppresses tumor metastasis. Conversely, its downregulation by TGFβ releases hnRNP M to initiate EMT-associated splicing changes. Restoring MASCOT expression significantly reduces metastatic burden in mouse models. Mechanistically, MASCOT scaffolds hnRNP M to nucleolin within the nucleolus, spatially sequestering hnRNP M away from the spliceosome. Our findings reveal a novel regulatory circuit that controls EMT-linked splicing and identify MASCOT as a promising RNA-based therapeutic candidate against metastatic progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336555 | GEO | 2026/08/04

REPOSITORIES: GEO

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Targeting the splicing factor hnRNP M with an endogenous circular RNA aptamer suppresses cancer metastasis

Project description:Alternative splicing (AS) is a key regulatory mechanism that expands transcriptomic diversity and is frequently hijacked by cancer cells to drive epithelial-mesenchymal transition (EMT), thereby promoting invasion and therapy resistance. However, therapeutic strategies to reprogram pathological AS networks remain limited. Here, we identified a circular RNA, MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ), that functions as an endogenous aptamer targeting the splicing factor hnRNP M, a central regulator of EMT-related AS reprogramming. As an endogenous repressor of hnRNP M, MASCOT maintains the epithelial status of cancer cells and suppresses tumor metastasis. Conversely, its downregulation by TGFβ releases hnRNP M to initiate EMT-associated splicing changes. Restoring MASCOT expression significantly reduces metastatic burden in mouse models. Mechanistically, MASCOT scaffolds hnRNP M to nucleolin within the nucleolus, spatially sequestering hnRNP M away from the spliceosome. Our findings reveal a novel regulatory circuit that controls EMT-linked splicing and identify MASCOT as a promising RNA-based therapeutic candidate against metastatic progression.

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Metastasis-repressive CircRNA MASCOT Regulates Distribution of the Splicing Factor hnRNP M

Project description:Alternative splicing (AS) diversifies the transcriptome complexity and is usually hijacked by cancer cells. Here, we identified heterogeneous nuclear ribonucleoprotein M (hnRNP M) as an indispensable contributor to EMT-related AS reprogramming, whose sub-nuclear distribution of hnRNP M is altered in metastatic tumors. Upon TGFβ stimulation, hnRNP M trends to disassociate with a circRNA called MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ) that demonstrated an impressive inhibitory effect on EMT process and tumor metastasis. Mechanistically, the anti-metastatic effect of MASCOT is attributed to not only its competition with U2 RNA splicing factors to recruit hnRNP M in the nucleoplasm, but also the anchorage of hnRNP M with nucleolin into the nucleolus to cause a temporospatial separation of hnRNP M from spliceosome. Moreover, the correlation between MASCOT expression and hnRNP M sub-nuclear localization was validated in clinical specimens. Our study deciphers the regulatory codes controlling AS networks and highlights MASCOT as a promising therapeutic to treat metastasis.

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