A stress granule-associated RNA-binding protein FAM120A drives cisplatin resistance in non-small cell lung cancer

Cisplatin-based chemotherapy is a standard treatment for non-small cell lung cancer (NSCLC), but drug resistance poses a major clinical challenge. Stress-adaptive mechanisms, such as stress granule (SG) formation, are increasingly recognized alternative pathways that facilitate cancer cell survival. Here, we identify the RNA-binding protein, family with sequence similarity 120A (FAM120A), as an SG-associated factor that drives cisplatin resistance in NSCLC. FAM120A expression was markedly elevated in cisplatin-resistant NSCLC cell lines and clinical tumor specimens and was essential for SG formation and cell survival following cisplatin-induced stress. We found that the intrinsically disordered RNA-binding domain of FAM120A is essential for its incorporation into SGs and for its cytoprotective function. Using enhanced cross-linking immunoprecipitation sequencing data and RNA immunoprecipitation-qPCR, we identified the long noncoding RNA, metastasis-associated lung adenocarcinoma transcript 1 as a key FAM120A interacting partner. MALAT1 levels were reduced upon FAM120A depletion, and overexpression of MALAT1 was sufficient to restore cisplatin resistance in these cells. These findings suggest that MALAT1 is an RNA species that is stabilized by FAM120A and involved in the cellular response to chemotherapy. Targeting this regulatory mechanism may offer new therapeutic strategies to overcome cisplatin resistance in NSCLC.