NDFIP1 limits cellular TAZ accumulation via exosomal sorting to inhibit NSCLC proliferation

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors, but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown. Besides, the WW domain containing proteins can be recognized by NDFIP1, resulted in the loading of the target proteins into exosomes. However, whether WW domain-containing transcription regulator 1 (WWTR1, also known as TAZ) can be packaged into exosomes by NDFIP1 and if so, whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent. Here, we first found that NDFIP1 was low expressed in NSCLC samples and cell lines, which is associated with shorter OS. Then, we confirmed the interaction between TAZ and NDFIP1, and the existence of TAZ in exosomes, which requires NDFIP1. Critically, knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate. And the cellular TAZ level could be altered by exosome secretion. Furthermore, NDFIP1 inhibited proliferation in vitro and in vivo, and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout. Moreover, TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples, and the serum exosomal TAZ level was lower in NSCLC patients. In summary, our data uncover a new tumor suppressor, NDFIP1 in NSCLC, and a new exosome-related regulatory mechanism of TAZ.

Automated summary

NDFIP1 has been identified as a tumor suppressor in multiple solid tumors, but its role in NSCLC and the mechanism involved are still unclear. This study found that NDFIP1 is downregulated in NSCLC samples and cell lines, which is associated with poor overall survival. Moreover, NDFIP1 interacts with TAZ and is required for the loading of TAZ into exosomes. Knockout of NDFIP1 leads to TAZ accumulation and altered cellular TAZ levels through exosome secretion. NDFIP1 also suppresses proliferation in NSCLC, and silencing TAZ reverses the increase in proliferation caused by NDFIP1 knockout. These findings highlight the tumor-suppressive role of NDFIP1 and the exosome-mediated regulation of TAZ in NSCLC.