The histone methyltransferase NSD3 enhances rDNA transcription in cancer

The histone methyltransferase NSD3 is one of the most recurrently amplified oncogenes in several cancer types and yet how NSD3 promotes tumorigenesis remains largely unknown. Most studies have focused on the short isoform of NSD3, lacking enzymatic activity while very little is known on the long NSD3 isoform, NSD3L, which also includes the SET methyltransferase domain. We found that NSD3L is a key regulator of ribosome biogenesis in cancer. NSD3L localises in the nucleolus and interacts with several nucleolar proteins. NSD3L overexpression is associated with enhanced expression of nucleolar genes and ribosomal RNA (rRNA) transcription in several tumour types. In cancer cells, but not in immortalised fibroblasts, NSD3L knock-down abrogates rRNA transcription and the binding to the entire sequence of ribosomal DNA of Polymerase I, as well as of the PolI activator upstream binding factor UBF, both required for rRNA transcription. Cut&Tag analyses demonstrated that NSD3 localises genome-wide on promoters. Conversely, on rDNA, NSD3L binds upstream of the rRNA transcription start site to a narrow sequence bound also by the FOS/JUN transcription factors. NSD3L deposits di- and tri- methyl groups to the histone lysine 36 on histone H3 throughout the entire rDNA sequences, competing with the histone methyltransferase SUV4-H20, thus preventing the deposition of the repressive histone mark H4K20me3. We propose NSD3L as one of the first chromatin remodelers actively promoting rRNA transcription and ribosome biogenesis. These findings usher novel therapeutic opportunities to target cancers presenting with NSD3 overexpression.