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A PSAT1 buff of YBX1 transcriptionally sustains HLA-E-mediated evasion of NK immunity.

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Title: A PSAT1 buff of YBX1 transcriptionally sustains HLA-E-mediated evasion of NK immunity.
Authors: Zhang, Yangyi1,2,3, Ren, He1,2, Ma, Chaobing1, Shi, Changhong4, Yang, Ruigang2, Wang, Chenxi2, Feng, Pengfei2, Zhang, Bo1,2, Liu, Chenyu1, Niu, Zubiao2, Yang, Yalan1, Zheng, You2, Sun, Zhuoran2, Zhang, Ying1, Zhang, Shinan1, Melino, Gerry5, Huang, Hongyan1,3 hhongy1999@126.com, Sun, Qiang2 sunq@bmi.ac.cn
Source: Proceedings of the National Academy of Sciences of the United States of America. 2025, Vol. 122 Issue 52, p1-11. 11p.
Subjects: Killer cells, Immunotherapy, Tumor microenvironment, Prostate cancer, Histocompatibility class I antigens, Genes
Abstract: Despite great success in certain cancers, immunotherapy made little progress in treating immune cold tumors, largely attributed to an immune-suppressive tumor microenvironment with elusive mechanisms. Here, we report in prostate cancer cells a positive feedback loop driven by phosphoserine aminotransferase 1 (PSAT1) that could be targeted to render effective cytotherapy by natural killer (NK) cells. In the loop, PSAT1 increases Y-box binding protein 1 (YBX1) phosphorylation by microtubule affinity-regulating kinase 2, promoting its nuclear translocation to upregulate PSAT1 transcription. Meanwhile, YBX1 also promotes human leukocyte antigens E (HLA-E) transcription to inactivate NK cells. Consequently, the PSAT1 loop serves as a buff sustaining YBX1/HLA-E expression, suppressing NK killing of prostate cancer cells. Targeting loop molecules, such as PAST1, effectively potentiates tumor suppression by NK cells both in-vitro and in-vivo. Thus, our study uncovered a heretofore unrecognized nonautonomous mechanism for PSAT1, as well as a molecular buff for YBX1, to drive tumor growth by evading NK immunity, providing a promising target for NK cytotherapy of immune cold tumors. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:Despite great success in certain cancers, immunotherapy made little progress in treating immune cold tumors, largely attributed to an immune-suppressive tumor microenvironment with elusive mechanisms. Here, we report in prostate cancer cells a positive feedback loop driven by phosphoserine aminotransferase 1 (PSAT1) that could be targeted to render effective cytotherapy by natural killer (NK) cells. In the loop, PSAT1 increases Y-box binding protein 1 (YBX1) phosphorylation by microtubule affinity-regulating kinase 2, promoting its nuclear translocation to upregulate PSAT1 transcription. Meanwhile, YBX1 also promotes human leukocyte antigens E (HLA-E) transcription to inactivate NK cells. Consequently, the PSAT1 loop serves as a buff sustaining YBX1/HLA-E expression, suppressing NK killing of prostate cancer cells. Targeting loop molecules, such as PAST1, effectively potentiates tumor suppression by NK cells both in-vitro and in-vivo. Thus, our study uncovered a heretofore unrecognized nonautonomous mechanism for PSAT1, as well as a molecular buff for YBX1, to drive tumor growth by evading NK immunity, providing a promising target for NK cytotherapy of immune cold tumors. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.2505658122