Conference / Meeting

Epigenetics Mondays Seminars - Alessandro Carrer Ph.D

Veneto Institute for Molecular Medicine (VIMM)
10 May 2021
Start time 
3:00 pm
Polo Ferrari 1 - Via Sommarive 5, Povo (Trento)
via zoom
Organizer: 
Dipartimento di Biologia Cellulare, Computazionale e Integrata - CIBIO
Target audience: 
University community
Attendance: 
Free
Contact person: 
Department of Cellular, Computational and Integrative Biology - CIBIO
Contact details: 
cibio.events@unitn.it

ATP-citrate lyase links metabolism and histone modification during pancreatic tumorigenesis

Mutant KRAS is thought to initiate pancreatic tumorigenesis, orchestrating a program that leads to cell de-differentiation, proliferation, and symbiotic cooperation with neighboring cells, enabling the cancer cells to thrive in a particularly harsh microenvironment. Recent studies have highlighted the role of metabolites in regulating the epigenome.  Although oncogenic Kras is known to reprogram cellular metabolism, the role of metabolic control of the epigenome in pancreatic tumorigenesis is poorly understood. The enzyme ATP-citrate lyase (ACLY) cleaves citrate to generate acetyl-CoA and serves as a primary source of acetyl-CoA for histone acetylation. We recently showed that expression of KrasG12D in mouse pancreas promotes elevated histone acetylation levels in pancreatic acinar cells, and that this precedes tumor development. We hypothesized that ACLY-dependent histone acetylation may play a role in facilitating pancreatic tumorigenesis. To test this, we generated mice deficient for Acly in pancreas (Pdx1-Cre; Aclyf/f mice). Surprisingly, the pancreas develops essentially normally in the absence of ACLY, and systemic metabolic homeostasis is intact. In the context of KrasG12D expression, ACLY deficiency reduces overall histone acetylation levels and suppresses tumor onset. ACLY deficiency also impairs pancreatitis-induced tumor development.  The work links oncogene-triggered metabolic reprogramming to the remodeling of the epigenome necessary for cellular transformation and tumor initiation.

Info:
cibio.events [at] unitn.it

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