Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

Lian, C.; Zhang, C.; Tian, P.; Tan, Q.; Wei, Y.; Zhang, Q.; Wang, Z.; Zhong, M.; Zhou, L.-Q.; Ke, X.; Zhang, H.; Zhu, Y.; Li, Z.; Cheng, J.; Wei, G.-H.

doi:10.1101/2023.11.28.569112

bioRxiv · 10.1101/2023.11.28.569112

Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

Lian, C.·Zhang, C.·Tian, P.·Tan, Q.·Wei, Y.·Zhang, Q.·Wang, Z.·Zhong, M.·Zhou, L.-Q.·Ke, X.·Zhang, H.·Zhu, Y.·Li, Z.·Cheng, J.·Wei, G.-H.

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Abstract

ZMYND11 encodes an epigenetic reader of histone methylation, functioning as a transcriptional corepressor. However, whether and how ZMYND11 contributes to cancer progression and therapy remains unclear. Here we report that ZMYND11 downregulation is prevalent in cancers and profoundly correlates with adverse prostate cancer patient outcomes. Depletion of ZMYND11 promotes tumor cell growth, migration and invasion in vitro as well as tumor formation and metastasis in vivo. Mechanistically, we find that ZMYND11 exhibits tumor suppressive roles through recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby squeezing HNRNPA1 in nucleus and inhibiting the formation of stress granules in cytoplasm. Furthermore, ZMYND11 antagonizes HNRNPA1-driven high PKM2/PKM1 ratio and counteracts PKM2-induced aggressive tumor phenotype. Remarkably, ZMYND11 recognition of HNRNPA1 could be disrupted by pharmaceutical inhibition of arginine methyltransferase PRMT5 while ZMYND11 low-expressing tumors are sensitive to the treatment of PRMT5 inhibitors. Collectively, our study unravels a novel and noncanonical function of ZMYND11 as the nonhistone methyl reader and discovers a mechanism for the requirement of arginine-methylation-mediated ZMYND11-HNRNPA1 association to restrict tumor progression and offers cancer therapeutic targets and potential biomarkers.

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Lian, C., Zhang, C., Tian, P., Tan, Q., Wei, Y., Zhang, Q., Wang, Z., Zhong, M., Zhou, L.-Q., Ke, X., Zhang, H., Zhu, Y., Li, Z., Cheng, J., Wei, G.-H.. 2023-11-30. Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity. https://doi.org/10.1101/2023.11.28.569112

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