Tumor suppressor SMAR1 regulates PKM alternative splicing by HDAC6-mediated deacetylation of PTBP1

Abstract Background Highly proliferating cancer cells exhibit the Warburg effect by regulation of PKM alternative splicing and promoting expression PKM2. Majority events are known to occur in nuclear matrix where various MARBPs actively participate events. SMAR1, being a MARBP an important tumor suppressor, is regulate cancer-associated genes. This study focuses on inhibition SMAR1. Methods Immunohistochemistry was performed breast patient samples establish correlation between SMAR1 isoform expression. Further, isoforms upon modulation cell lines quantified qRT-PCR western blot. The acetylation status PTBP1 estimated immunoprecipitation along with its enrichment pre-mRNA CLIP knockdown conditions. role metabolism tumorigenesis explored vitro enzymatic assays functional knockdown. Besides, vivo formation injecting adeno-SMAR1-transduced MDA-MB-231 NOD/SCID mice performed. Results profile patients revealed that has inverse PKM2 positive PKM1. Further quantitative also reflects promotes PKM1 over tumorigenic deacetylates via recruitment HDAC6 resulting reduced pre-mRNA. inhibits effect, potential cells, generation PKM2-dependent manner. Conclusions regulates causing HDAC6-dependent deacetylation PTBP1, Additionally, suppresses glucose utilization lactate production repression suggests suppressor properties splicing.