LAUSR

Simple Summary Cancer stem cells (CSCs) are a small population of tumour cells bearing stemness characteristics. They have been deemed as a root of cancer development and a promising drug target for anticancer therapy. Herein, we discuss the roles of an RNA-binding protein, Lin28, in regulating cancer cell stemness to drive tumour progression. Lin28 acts on various types of RNAs in cancer cells and regulates these RNA functions to control the expression of oncogenes. In these ways, Lin28 promotes cancer cell survival, growth, and invasion. We also discuss recent efforts in developing Lin28 inhibitors targeting CSCs in tumours. Abstract Tumours develop therapy resistance through complex mechanisms, one of which is that cancer stem cell (CSC) populations within the tumours present self-renewable capability and phenotypical plasticity to endure therapy-induced stress conditions and allow tumour progression to the therapy-resistant state. Developing therapeutic strategies to cope with CSCs requires a thorough understanding of the critical drivers and molecular mechanisms underlying the aforementioned processes. One such hub regulator of stemness is Lin28, an RNA-binding protein. Lin28 blocks the synthesis of let-7, a tumour-suppressor microRNA, and acts as a global regulator of cell differentiation and proliferation. Lin28also targets messenger RNAs and regulates protein translation. In this review, we explain the role of the Lin28/let-7 axis in establishing stemness, epithelial-to-mesenchymal transition, and glucose metabolism reprogramming. We also highlight the role of Lin28 in therapy-resistant prostate cancer progression and discuss the emergence of Lin28-targeted therapeutics and screening methods.