HMGA1 promotes the progression of lung adenocarcinoma through the STAT1-mediated transcriptional activation of DDAH1.

Abstract

Background: Advancements in precision oncology have generated increased interest in the prognostic and therapeutic capabilities of transcription factors, among which HMGA1 is significantly correlated with LUAD prognosis. However, our understanding of HMGA1 remains insufficient. This study seeks to elucidate the biological functions of HMGA1 and to investigate the underlying mechanisms.

Methods: The prognostic value of HMGA1 was validated across multiple independent patient cohorts with LUAD, and its impact on tumor proliferation was verified by both in vitro and in vivo models. A series of experiments were performed to investigate the underlying molecular mechanism, including RNA sequencing, co-immunoprecipitation and chromatin immunoprecipitation.

Results: HMGA1 plays a crucial role in promoting the proliferation of LUAD. The underlying mechanism involves the recruitment of STAT1 to the promoter region of DDAH1, which synergistically increases its transcription and subsequently activates the ADMA/NO signaling pathway. Notably, the STAT1 inhibitor fludarabine has been shown to effectively impede the progression of LUAD models characterized by high levels of HMGA1.

Conclusion: Our research reveals a previously unrecognized mechanism through which the HMGA1/STAT1 complex facilitates LUAD proliferation by transcriptionally activating DDAH1. Moreover, we propose that fludarabine could serve as a promising therapeutic option for LUAD patients exhibiting elevated levels of HMGA1.