KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia

Abstract

KDM3B reportedly shows both tumor-suppressive and tumor-promoting activities in leukemia. The function of KDM3B is likely cell-type dependent and its seeming functional discordance may reflect its phenotypic dependence on downstream targets. Here, we first showed the underexpression of KDM3B in acute myeloid leukemia (AML) patients and AML cell lines with MLL-AF6/9 or PML-RARA translocations. Overexpression of KDM3B repressed colony formation of AML cell line with 5q deletion. We then performed global microarray profiling to identify potential downstream targets of KDM3B, notably HOXA1, which was verified by real time PCR and Western blotting. We further showed KDM3B binding at retinoic acid response elements (RARE) but not at the promoter region of HOXA1 gene. KDM3B knockdown resulted in increased mono-methylation but decreased di-methylation of H3K9 at RARE while eschewing the promoter region of HOXA1. Collectively, we found that KDM3B exhibits potential tumor-suppressive activity and transcriptionally modulates HOXA1 expression via RARE in AML.

Keywords:

• Histone demethylation
• MLL-rearrangement
• PML-RARA translocations

Acknowledgements

The authors would like to thank Sonja Eberth who gave suggestions about ChIP design, Maren Kaufmann, Corinna Meyer, Margarete Zaborski, and Vivian Hauer for technical support. The research was supported by the Alexander von Humboldt Foundation and funded by the National Natural Science Foundation of China (NSFC) grants [#81370628, #81570157], the Scientific Research Foundation for the Returned Overseas Chinese Scholars State Education Ministry, Shandong Provincial Natural Science Foundation, China [#ZR2015CL023], and Shandong Province Higher Educational Science and Technology Program [J16LL54].

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1324156.

Additional information

Funding

The research was supported by the Alexander von Humboldt Foundation and funded by the National Natural Science Foundation of China (NSFC) grants [#81370628, #81570157], the Scientific Research Foundation for the Returned Overseas Chinese Scholars from State Education Ministry, China, Shandong Provincial Natural Science Foundation, China [#ZR2015CL023], and Shandong Province Higher Educational Science and Technology Program [J16LL54].