Evidence map›Paper›PMID 39713466›Full record

ArticlebioRxiv : the preprint server for biology2024

Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Pornlada Likasitwatanakul, Zhixin Li, Paul Doan, Sandor Spisak, Akhouri Kishore Raghawan, Qi Liu, Priscilla Liow, Sunwoo Lee, David Chen, Pratyusha Bala and 10 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Pornlada LikasitwatanakulDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0002-9689-3231
Zhixin LiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0001-9962-3942
Paul DoanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0002-7329-3495
Sandor SpisakDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Akhouri Kishore RaghawanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Qi LiuDepartment of Medicine, Harvard Medical School, Boston, MA, USA.
Priscilla LiowDepartment of Medicine, Harvard Medical School, Boston, MA, USA.
Sunwoo LeeDepartment of Medicine, Harvard Medical School, Boston, MA, USA.
David ChenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Pratyusha BalaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Pranshu SahgalDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Daulet AitymbayevDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jennifer S ThalappillilDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Malvina PapanastasiouBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
William HawkinsBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
Steven A CarrBroad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
Haeseong ParkDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
James M ClearyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jun QiDepartment of Medicine, Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-1461-3356
Nilay S SethiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID 0000-0002-3748-7559

Funding

VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI Irene M. Ghobrial · 1985 to 2026
$330.6M
STRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4M
Molecular mechanisms of developmental reprogramming in colorectal cancerR01CA292507 · NCI · DANA-FARBER CANCER INST · PI Nilay Sethi · 2024 to 2026
$2.8M
NCI NIH HHS P30 CA006516NCI NIH HHS R01 CA292507NIDDK NIH HHS P30 DK034854
6 · The paper itself

Abstract

Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.

Indexed as

colorectal cancerepigenetic regulationintestinal differentiationstem cell

Identifiers

PMID39713466
PMCPMC11661112

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.