Acetylation regulates the nucleocytoplasmic distribution and oncogenic function of karyopherin alpha 2 in lung adenocarcinoma

by Selleckchem | Sep 18 2023

Karyopherin subunit alpha 2 (KPNA2, importin α1) is a nucleoplasmic protein responsible for the nuclear import of proteins with classical nuclear localization signals. Aberrant nuclear accumulation of KPNA2 has been observed in numerous cancer tissues. AMP-activated protein kinase (AMPK) is involved in the phosphorylation and acetylation of KPNA2 in enterocytes. However, the impact of these post-translational modifications on modulating the nucleocytoplasmic distribution of KPNA2 and its oncogenic role remain unclear. Unlike nuclear accumulation of wild-type KPNA2, which promoted lung cancer cell migration, KPNA2 Lys22 acetylation-mimicking mutations (K22Q and K22Q/S105A) prevented nuclear localization of KPNA2 and reduced the cell migration ability. Cytosolic KPNA2 K22Q interacted with and restricted the nuclear entry of E2F transcription factor 1 (E2F1), an oncogenic cargo protein of KPNA2, in lung cancer cells. Intriguingly, the AMPK activator EX229 promoted the nuclear export of KPNA2 S105A. However, the CBP/p300 inhibitor CCS-1477 abolished this phenomenon, suggesting that CBP/p300-mediated acetylation of KPNA2 promoted KPNA2 nuclear export in lung cancer cells. Collectively, our findings suggest that the CBP/p300 positively regulates KPNA2 acetylation, which enhances its cytosolic localization and suppresses its oncogenic activity in lung cancer.

Comments:

The passage you provided describes the role of Karyopherin subunit alpha 2 (KPNA2), also known as importin α1, in nuclear import of proteins with classical nuclear localization signals. Abnormal accumulation of KPNA2 has been observed in various cancer tissues. The passage discusses the impact of post-translational modifications on KPNA2 and its role in cancer.

The passage mentions that AMP-activated protein kinase (AMPK) is involved in the phosphorylation and acetylation of KPNA2 in enterocytes. However, the specific effects of these modifications on the nucleocytoplasmic distribution of KPNA2 and its oncogenic role are not yet clear.

The passage further explains that while the wild-type KPNA2 promotes lung cancer cell migration through nuclear accumulation, acetylation-mimicking mutations at Lys22 (K22Q and K22Q/S105A) prevent the nuclear localization of KPNA2 and reduce cell migration ability. This suggests that acetylation at Lys22 is important for regulating the nucleocytoplasmic distribution of KPNA2 and its oncogenic properties in lung cancer.

Additionally, it is mentioned that cytosolic KPNA2 K22Q interacts with and restricts the nuclear entry of E2F transcription factor 1 (E2F1), which is an oncogenic cargo protein of KPNA2 in lung cancer cells. This indicates that the acetylation-mimicking mutation affects the interaction of KPNA2 with its cargo protein, thereby influencing its cellular localization and oncogenic activity.

The passage also highlights the role of AMPK activator EX229 in promoting the nuclear export of KPNA2 S105A. However, this phenomenon is abolished by the CBP/p300 inhibitor CCS-1477, suggesting that acetylation of KPNA2 by CBP/p300 promotes its nuclear export in lung cancer cells. This implies that CBP/p300 positively regulates the acetylation of KPNA2, leading to enhanced cytosolic localization and suppression of its oncogenic activity in lung cancer.

In summary, the passage provides insights into the role of KPNA2 and its post-translational modifications, such as acetylation, in regulating its nucleocytoplasmic distribution and oncogenic properties in lung cancer. It suggests that acetylation of KPNA2 by CBP/p300 promotes its cytosolic localization and suppresses its oncogenic activity in lung cancer cells.