Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Department of Urology, University of California, San Francisco, CA, USA.
Nat Cell Biol. 2023 Jun;25(6):892-903. doi: 10.1038/s41556-023-01141-9. Epub 2023 May 8.
Cancer cells often co-opt post-transcriptional regulatory mechanisms to achieve pathologic expression of gene networks that drive metastasis. Translational control is a major regulatory hub in oncogenesis; however, its effects on cancer progression remain poorly understood. Here, to address this, we used ribosome profiling to compare genome-wide translation efficiencies of poorly and highly metastatic breast cancer cells and patient-derived xenografts. We developed dedicated regression-based methods to analyse ribosome profiling and alternative polyadenylation data, and identified heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a translational controller of a specific mRNA regulon. We found that HNRNPC is downregulated in highly metastatic cells, which causes HNRNPC-bound mRNAs to undergo 3' untranslated region lengthening and, subsequently, translational repression. We showed that modulating HNRNPC expression impacts the metastatic capacity of breast cancer cells in xenograft mouse models. In addition, the reduced expression of HNRNPC and its regulon is associated with the worse prognosis in breast cancer patient cohorts.
癌细胞经常会采用转录后调控机制来病理性地表达驱动转移的基因网络。翻译调控是致癌过程中的主要调控枢纽；然而，其对癌症进展的影响仍知之甚少。在这里，为了解决这个问题，我们使用核糖体谱分析比较了低转移和高转移乳腺癌细胞和患者来源异种移植物的全基因组翻译效率。我们开发了专门的基于回归的方法来分析核糖体谱和可变多聚腺苷酸化数据，并确定异质核核糖核蛋白 C (HNRNPC) 是特定 mRNA 调节子的翻译控制器。我们发现 HNRNPC 在高转移性细胞中下调，导致 HNRNPC 结合的 mRNA 发生 3'非翻译区延长，随后翻译受到抑制。我们表明，调节 HNRNPC 的表达会影响异种移植小鼠模型中乳腺癌细胞的转移能力。此外，HNRNPC 及其调节子的表达减少与乳腺癌患者队列的预后较差相关。
