The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway

Wang, S.-P.; Yeh, L.-W.; Chen, J.-W.; Yeh, J.-Y.; Kao, M.-H.; Hong, H.-C.; Wu, S.; Cheung, W.-M.; Liu, T.-Y.; Aberin, M. A. E.; Paas-Oliveros, E.; Escajeda, A.; Shih, E.; Tarn, W.-Y.; Chang, Y.-M.; Wang, L.-H.

doi:10.1101/2024.05.31.596824

bioRxiv · 10.1101/2024.05.31.596824

The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway

Wang, S.-P.·Yeh, L.-W.·Chen, J.-W.·Yeh, J.-Y.·Kao, M.-H.·Hong, H.-C.·Wu, S.·Cheung, W.-M.·Liu, T.-Y.·Aberin, M. A. E.·Paas-Oliveros, E.·Escajeda, A.·Shih, E.·Tarn, W.-Y.·Chang, Y.-M.·Wang, L.-H.

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Abstract

Histone H3K27 demethylase UTX (aka KDM6A) is mutated in many human cancers, suggesting its tumor suppressive role during cancer development. However, most tumors still express wild-type UTX/KDM6A and its function is not always linked to tumor suppression. Here, we present evidence of UTX/KDM6As role in sustaining tumor growth, revealing its function in tumor maintenance. We find that UTX/KDM6A sustains tumor cell cycling and survival via regulating DNA replication-associated transcriptional programs in a demethylase-independent manner. UTX/KDM6A can also interact with PARP1 and facilitate its recruitment to DNA lesions. Therefore, UTX/KDM6A depletion disrupts DNA replication and repair pathways, activating ATM-CHK2 and ATR-CHK1 signaling pathways and triggering S and G2/M checkpoints, leading to a pronounced defect in tumor growth. Analysis of human cancer xenograft models further demonstrates that knockdown of UTX/KDM6A by RNA-interference, rather than inhibition of its enzymatic activity via GSK-J4, shows potent anticancer effects. Dual inhibition of UTX/KDM6A and ATR further demonstrates synergistic anticancer activities. Our work highlights UTX/KDM6A as a potential therapeutic target for cancer treatment, especially when combined with ATR inhibition. HighlightsO_LIUTX/KDM6A contributes to tumor maintenance by promoting the growth and survival of tumor cells C_LIO_LITumor cells rely on UTX/KDM6A to maintain DNA replication, cell cycling, and DNA damage repair C_LIO_LIUTX/KDM6A depletion triggers S and G2/M checkpoints via activating ATM-CHK2 and ATR-CHK1 signaling pathways C_LIO_LITargeting UTX/KDM6A may prove to be an innovative strategy for cancer therapy, whether employed independently or in conjunction with ATR inhibitors. C_LI The Paper ExplainedO_ST_ABSProblemC_ST_ABSThe aggressive growth of tumors relies significantly on heightened proliferation rates and genomic instability, which necessitate robust DNA replication machinery and efficient DNA damage repair mechanisms for tumor cell survival and proliferation. UTX/KDM6A, a histone demethylase central to chromatin and epigenetic regulation, is commonly mutated in various human cancers. However, its role as a tumor suppressor or promoter remains unclear across different cancer contexts. This study delves into the potential tumor-maintaining role of UTX/KDM6A in cancer progression and tumorigenesis, establishing the mechanistic foundation for its tumor-promoting function. ResultsWe uncover UTX/KDM6As crucial role in tumor maintenance via its participation in DNA replication and repair pathways. Surprisingly, we find that its histone demethylase activity is dispensable for these functions, implying an alternative role as a scaffold protein. Consequently, our findings suggest that targeting the entire UTX/KDM6A gene or protein, rather than inhibiting its enzymatic activity, holds promise as a therapeutic strategy for tumors dependent on its tumor-maintaining function. ImpactThis study unveils UTX/KDM6As multifaceted role in cancer progression, shedding light on its diverse contributions to tumorigenesis. Our findings suggest promising therapeutic strategies for cancer treatment, highlighting the importance of targeting UTX/KDM6A and its impact on DNA replication and repair pathways. These discoveries set the stage for further exploration of UTX/KDM6A-mediated mechanisms in clinical settings, indicating potential applications in future clinical trials and combination therapy strategies.

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Wang, S.-P., Yeh, L.-W., Chen, J.-W., Yeh, J.-Y., Kao, M.-H., Hong, H.-C., Wu, S., Cheung, W.-M., Liu, T.-Y., Aberin, M. A. E., Paas-Oliveros, E., Escajeda, A., Shih, E., Tarn, W.-Y., Chang, Y.-M., Wang, L.-H.. 2024-06-03. The tumor-maintaining function of UTX/KDM6A in DNA replication and the PARP1-dependent repair pathway. https://doi.org/10.1101/2024.05.31.596824

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