Table 1.

Brd4 mediated programmed cell death Pathways.

Target substrates	Cooperates with transcriptional regulator		Regulation by Brd4	Signaling pathway	Cellular type	BETi	Ref.
Apoptosis
(1) Pro-apoptotic proteins
NOXA		P53	Down, mRNA, direct	P53	Acute myeloid leukemia	CPI203, JQ1	[41, 42]
PUMA		P53	Down, mRNA, direct	P53	Acute myeloid leukemia	CPI203, JQ1	[41, 42]
BIM		miR17–92	Down, mRNA, indirect	BCL-2	Eµ-Myc lymphoma, MM.1 S, HL-60 and MV4;11	JQ1	[44, 45]
CHOP		miR-146a	Down, mRNA, indirect	DR5	Colorectal cancer cells	JQ1, I-BET151, I-BET762, OTX015	[48, 49]
FoxO4		N/A	Up, mRNA, indirect	PI3K/AKT	Renal epithelial cells	JQ1	[68]
(2) Anti-apoptotic proteins
BCL-2		N/A	Up, mRNA, direct	BCL-2	Mixed-lineage leukemia, T cell acute lymphoblastic leukemia	JQ1, I-BET151	[29, 38]
BCL-XL		MED1	Up, mRNA, direct	BCL-2	Multiple myeloma	JQ1	[4]
MCL-1		MED1	Up, mRNA, direct and Protein stability	BCL-2	Multiple myeloma	JQ1, ZBC260, dBET	[4, 40]
LIVIN		N/A	Up, mRNA, direct	FAS	Refractory lymphoma cells	JQ1, ARV-825	[51]
cFLIP		N/A	Up, mRNA, direct	Caspase 8	Non-small cell lung cancer	JQ1, I-BET762, OTX015	[59]
XIAP		N/A	Up, mRNA, direct	Caspase 8, 3, 7	Non-small cell lung cancer	JQ1, I-BET762, OTX015	[59]
Survivin		NF-κB	Up, mRNA, direct	Caspase 3, 7	Glioblastoma cells	JQ1, I-BET151, I-BET762	[58]
cIAP2		NF-κB	Up, mRNA, direct	NF-κB	Gastric cancer cells	JQ1	[57]
Caveolin-1		N/A	Down, Protein	AKT	cardiomyocytes	JQ1	[69]
Autophagy
Autophagosome formation genes, e.g., BECN1, AP1LC3B		G9a	Down, mRNA, direct	mTORC	Pancreatic adenocarcinoma cells	JQ1, I-BET762, OTX015	[13]
Autophagolysosome formation genes, e.g., PLEKHM1, TECPR1		G9a	Down, mRNA, direct	mTORC	Pancreatic adenocarcinoma cells	JQ1, I-BET762, OTX015	[13]
Lysosome genes, e.g., GNS, SGSH, TPP1		G9a	Down, mRNA, direct	mTORC	Pancreatic adenocarcinoma cells	JQ1, I-BET762, OTX015	[13]
AMPK		N/A	Suppress its activity	mTORC	Breast cancer cells	9 f (FL-411)	[14]
Necroptosis
MLKL		IRF1/ P-TEFb	Up, mRNA, direct	RIPK1/RIPK3/ MLKL	HT29, L929	JQ1, I-BET151, I-BET762	[98]
Pyroptosis
NAIP2, 5, 6		IRF8-PU.1	Up, mRNA, direct	NLRC4	BMDM	N/A	[31]
NAIP1, NLRC4		N/A	Up, mRNA, indirect	NLRC4	BMDM	N/A	[31]
pro-IL-18		N/A	Up, mRNA, direct	NLRC4	BMDM	N/A	[31]
Cleaved IL-1β and Casp-1		N/A	Up, Protein	NLRP3/caspase11	BMDM	N/A	[31]
Cleaved IL-1β and Casp-1		N/A	Up, Protein	Pyrin	BMDM	N/A	[31]
NLRP3		NF-κB	Down, mRNA, direct	NLRP3/caspase1	Renal cell carcinoma	JQ1	[15]
NLRP3		N/A	Up, Protein	NLRP3/caspase1	Glial cells, colon or liver tissues	JQ1	[111, 112, 116]
Ferroptosis
FTH1		N/A	Up, protein stability	Ferritinophagy	Breast cancer, lung squamous cell carcinoma	JQ1	[16]
GPX4		N/A	Up, mRNA, indirect	Ferritinophagy	Breast cancer, lung squamous cell carcinoma	JQ1	[16]
SLC7A11		N/A	Up, mRNA, indirect	Ferritinophagy	Breast cancer, lung squamous cell carcinoma	JQ1	[16]
SLC3A2		N/A	Up, mNRA, direct	Ferritinophagy	Breast cancer, lung squamous cell carcinoma	JQ1	[16]