HHIPL2 positively governs Hedgehog signaling to accelerate non-small cell lung cancer progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization

Sonic Hedgehog signaling is aberrantly activated in non-small cell lung cancer (NSCLC). However, the regulatory molecules of Sonic Hedgehog signaling during NSCLC development are still largely unknown. Here, we demonstrated that HHIP Like 2 (HHIPL2) is a crucial Sonic Hedgehog signaling regulator, accelerating NSCLC progression via positively governing Sonic Hedgehog signaling. Clinically, HHIPL2 is highly expressed in NSCLC and indicates a poor prognosis. Consistently, via depletion or gain of HHIPL2 in vivo and in vitro, we identified its oncogenic role in NSCLC proliferation and metastasis. Mechanistically, HHIPL2 interacted with the RNA-binding protein HNRNPC to alter its nucleo-cytoplasmic translocation. HHIPL2-regulated HNRNPC accumulation in the cytoplasm promoted the mRNA stability of HNF1A, a transcription factor for SHH, which subsequently enhanced the Sonic Hedgehog signaling activity to facilitate NSCLC progression. Furthermore, we discovered that triptolide (TPL), an HNF1A inhibitor, impeded HHIPL2-mediated Sonic Hedgehog signaling activation and NSCLC malignancy. Therefore, our findings not only uncover a previously unrecognized role for HHIPL2 in regulating the Sonic Hedgehog signaling pathway but also highlight a novel HHIPL2/HNRNPC/HNF1A axis as an attractive target for NSCLC therapy. Schematic diagram (created by Figdraw.com) showing that HHIPL2 positively governs Hedgehog signaling to accelerate NSCLC progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization.