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Int J Biol Sci 2024; 20(6):1978-1991. doi:10.7150/ijbs.91867 This issue Cite

Research Paper

BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1

Guowen Ren1,*, Jinghong Chen1,3,*, Yue Pu1,*, Eun Ju Yang1, Shishi Tao1, Pui Kei Mou1, Li-Jie Chen1, Wenli Zhu4, Kin Long Chan4, Guanghui Luo4, Chuxia Deng1,2, Joong Sup Shim1,2,✉

1. Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
2. MOE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, China.
3. Central laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
4. Kiang Wu Hospital, Macau SAR, China.
*These authors contributed equally to this work.

✉ Corresponding author: Joong Sup Shim. Tel.: +853 8822 4990; E-mail address: jsshimedu.mo.

Citation:
Ren G, Chen J, Pu Y, Yang EJ, Tao S, Mou PK, Chen LJ, Zhu W, Chan KL, Luo G, Deng C, Shim JS. BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. Int J Biol Sci 2024; 20(6):1978-1991. doi:10.7150/ijbs.91867. https://www.ijbs.com/v20p1978.htm
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Abstract

Graphic abstract

Loss of PTEN tumor suppressor is an important event during colorectal cancer (CRC) development and is a target for therapeutic exploitation. This study reports that bromodomain and extra-terminal motif (BET) is a synthetic lethal partner of PTEN in CRC. BET inhibition (BETi) selectively induced G1 cell cycle arrest and apoptosis in PTEN-/- CRC. Further, BETi selectively and dose-dependently suppressed the growth of PTEN-/- CRC tumor xenografts in mice and patient-derived organoids. Mechanistically, PTEN-deficient CRC cells elevated the level of cytoplasmic p21CIP1/WAF1 that is hyper-phosphorylated at Thr145 by AKT. BETi suppressed AKT activation in PTEN-deficient CRC cells, followed by the reduction in p21 phosphorylation at Thr145, thereby promoting its nuclear translocation. In addition, BETi suppressed MYC level and this in turn increased the total p21 level in the nuclei. Over-expression of a phospho-mimetic p21 mutant (T145D) significantly rescued the BETi effect on PTEN-deficient CRC. These results suggest that BETi has a dual action on p21: elevating the level of p21 by inhibiting MYC and converting the oncogenic (cytoplasmic) p21 into the tumor-suppressive (nuclear) p21 by inhibiting AKT. Taken together, this study identified the synthetic lethal interaction between PTEN and BET, and provides a potential actionable target for CRC with PTEN loss.

Keywords: Colorectal cancer, PTEN, synthetic lethality, BET, MYC, p21, AKT, Phosphorylated p21 at Thr145

Citation styles

APA
Ren, G., Chen, J., Pu, Y., Yang, E.J., Tao, S., Mou, P.K., Chen, L.J., Zhu, W., Chan, K.L., Luo, G., Deng, C., Shim, J.S. (2024). BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. International Journal of Biological Sciences, 20(6), 1978-1991. https://doi.org/10.7150/ijbs.91867.

ACS
Ren, G.; Chen, J.; Pu, Y.; Yang, E.J.; Tao, S.; Mou, P.K.; Chen, L.J.; Zhu, W.; Chan, K.L.; Luo, G.; Deng, C.; Shim, J.S. BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. Int. J. Biol. Sci. 2024, 20 (6), 1978-1991. DOI: 10.7150/ijbs.91867.

NLM
Ren G, Chen J, Pu Y, Yang EJ, Tao S, Mou PK, Chen LJ, Zhu W, Chan KL, Luo G, Deng C, Shim JS. BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. Int J Biol Sci 2024; 20(6):1978-1991. doi:10.7150/ijbs.91867. https://www.ijbs.com/v20p1978.htm

CSE
Ren G, Chen J, Pu Y, Yang EJ, Tao S, Mou PK, Chen LJ, Zhu W, Chan KL, Luo G, Deng C, Shim JS. 2024. BET inhibition induces synthetic lethality in PTEN deficient colorectal cancers via dual action on p21CIP1/WAF1. Int J Biol Sci. 20(6):1978-1991.

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