The interaction between mRNA and ribosomal RNA (rRNA) transcription in cancer remains unclear. RNAP I and II possess a common N-terminal tail (NTT), RNA polymerase subunit RPB6, which interacts with P62 of transcription factor (TF) IIH, and is a common target for the link between mRNA and rRNA transcription. The mRNAs and rRNAs affected by FUBP1-interacting repressor (FIR) were assessed via RNA sequencing and qRT-PCR analysis. An FIR, a c-myc transcriptional repressor, and its splicing form FIRΔexon2 were examined to interact with P62. Protein interaction was investigated via isothermal titration calorimetry measurements. FIR was found to contain a highly conserved region homologous to RPB6 that interacts with P62. FIRΔexon2 competed with FIR for P62 binding and coactivated transcription of mRNAs and rRNAs. Low-molecular-weight chemical compounds that bind to FIR and FIRΔexon2 were screened for cancer treatment. A low-molecular-weight chemical, BK697, which interacts with FIRΔexon2, inhibited tumor cell growth with rRNA suppression. In this study, a novel coactivation pathway for cancer-related mRNA and rRNA transcription through TFIIH/P62 by FIRΔexon2 was proposed. Direct evidence in X-ray crystallography is required in further studies to show the conformational difference between FIR and FIRΔexon2 that affects the P62–RBP6 interaction.

Post-translational modification (PTM) of histones dynamically regulates gene transcription and is closely related to cancer development. Altering the epigenome is thus a promising strategy for cancer chemotherapy. However, there have been no methods to artificially introduce physiologically relevant histone PTMs and their transcription profile without genetic engineering in living cells. Here we report a cell-permeable histone acetylation catalyst, BAHA-LANA-PEG-CPP44, enabling cancer epigenome manipulation. The catalyst selectively entered leukemia cells, bound to chromatin, and selectively acetylated H2BK120 of endogenous histones in a short reaction time. The catalytic histone acetylation attenuated chromatin binding of negative elongation factor E (NELFE), an RNA polymerase II regulatory factor, and changed the transcription profile in leukemia cells. The in-cell chemical catalysis slowed proliferation of leukemia cells and reduced their tumorigenic potential in mice. As this approach requires no genetic engineering and is orthogonal to canonical epigenetic drugs, it may represent a new modality of cancer chemotherapy.