TNPO1-mediated nuclear import of ARID1B promotes tumor growth in ARID1A-deficient gynecologic cancer

摘要

Karyopherin-beta proteins are critically involved in cancer progression and have been reported as potential biomarkers and therapeutic targets for tumor treatment. However, TNPO1, as an important karyopherin-beta family member, underlying functional roles in cancers remain largely unclear. In this study, under integrated geneexpression profiling screen of karyopherin-beta in gynecologic cancer, we identify TNPO1 as a pivotal contributor to the gynecologic cancer progression. Remarkably, ARID1A-deficient gynecologic cancer cells are specifically vulnerable to the genetic perturbations of TNPO1 in vitro and in vivo. Mechanistically, TNPO1 is selectively responsible for nuclear import of ARID1B, which is a synthetic lethal target in ARID1A-inactivating mutation cancers. Furthermore, TNPO1 or ARID1B knockdown changes chromatin accessibility that results in loss of H3K4me1 and H3K27ac marker, diminishing activated transcription factor of the AP-1 family, and inactivating the PI3K/AKT signaling pathway by reducing growth pathway genes expression including PIK3CA and FGFR2. Together, this work indicates that the oncogenic function of TNPO1 and maybe represent a novel therapeutic strategy to treat ARID1A-deficient gynecologic cancer.