Schematic overview of the cellular and molecular mechanisms involved in the cancer progression, including the proposed cellular and molecular mechanisms in cancer cells trajectory. AT1: alveolar type 1 cells; AT2: alveolar type 2 cells; AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; IA: invasive adenocarcinoma; EMT: epithelial-mesenchymal transition

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	Gene summary
	Malignant transformation analysis
	Malignant transformation related pathway analysis
	Cell-cell communication analysis
	Single-cell gene regulatory network inference analysis
	Somatic mutation of malignant transformation related genes
	Related drugs of malignant transformation related genes

Gene: HDAC4

Gene summary for HDAC4

Gene summary.

Gene information	Species	Human
	Gene symbol	HDAC4
	Gene ID	9759
	Gene name	histone deacetylase 4
	Gene Alias	AHO3
	Cytomap	2q37.3
	Gene Type	protein-coding
	GO ID	GO:0000003
	UniProtAcc	P56524

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Malignant transformation analysis

Identification of the aberrant gene expression in precancerous and cancerous lesions by comparing the gene expression of stem-like cells in diseased tissues with normal stem cells

Malignant transformation involving gene list.

Entrez ID	Symbol	Replicates	Species	Organ	Tissue	Adj P-value	Log2FC	Malignancy
9759	HDAC4	CCI_2	Human	Cervix	CC	2.31e-03	5.00e-01	0.5249
9759	HDAC4	CCI_3	Human	Cervix	CC	1.47e-05	6.23e-01	0.516
9759	HDAC4	NAFLD1	Human	Liver	NAFLD	1.98e-02	5.04e-01	-0.04
9759	HDAC4	HCC1_Meng	Human	Liver	HCC	4.74e-05	-1.14e-01	0.0246
9759	HDAC4	HCC2_Meng	Human	Liver	HCC	2.06e-03	-6.55e-02	0.0107
9759	HDAC4	S014	Human	Liver	HCC	8.47e-10	6.24e-01	0.2254
9759	HDAC4	S015	Human	Liver	HCC	7.41e-07	5.71e-01	0.2375
9759	HDAC4	S016	Human	Liver	HCC	2.29e-14	6.51e-01	0.2243
9759	HDAC4	HTA12-23-1	Human	Pancreas	PDAC	8.51e-05	6.60e-01	0.3405
9759	HDAC4	HTA12-25-1	Human	Pancreas	PDAC	3.87e-06	6.43e-01	0.313
9759	HDAC4	HTA12-26-1	Human	Pancreas	PDAC	2.77e-17	7.41e-01	0.3728
9759	HDAC4	HTA12-29-1	Human	Pancreas	PDAC	2.08e-21	5.38e-01	0.3722

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Cervix		CC: Cervix cancer
		HSIL_HPV: HPV-infected high-grade squamous intraepithelial lesions
		N_HPV: HPV-infected normal cervix
Liver		HCC: Hepatocellular carcinoma
		NAFLD: Non-alcoholic fatty liver disease

∗log2FC in expression of this searched gene in stem-like cells from each diseased tissue sample relative to stem-like cells in normal samples in each tissue plotted against the malignancy continuum. Samples are colored based on if they are from different disease stage.

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Malignant transformation related pathway analysis

Find out the enriched GO biological processes and KEGG pathways involved in transition from healthy to precancer to cancer

Figure of enriched GO biological processes.

Tissue	Disease Stage	Enriched GO biological Processes
Colorectum	AD
Colorectum	SER
Colorectum	MSS
Colorectum	MSI-H
Colorectum	FAP

∗Top 15 enriched GO BP terms are showed in the bar plot of each disease state in each tissue. Each row represents a significant GO biological process which is colored according to the -log10(p.adjust).

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Enriched GO biological processes.

GO ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	Count
GO:00434676	Liver	NAFLD	regulation of generation of precursor metabolites and energy	26/1882	130/18723	4.78e-04	6.78e-03	26
GO:00714967	Liver	NAFLD	cellular response to external stimulus	51/1882	320/18723	6.21e-04	8.18e-03	51
GO:00510987	Liver	NAFLD	regulation of binding	56/1882	363/18723	7.80e-04	9.77e-03	56
GO:0062014	Liver	NAFLD	negative regulation of small molecule metabolic process	21/1882	102/18723	1.09e-03	1.27e-02	21
GO:00433937	Liver	NAFLD	regulation of protein binding	34/1882	196/18723	1.11e-03	1.28e-02	34
GO:0045820	Liver	NAFLD	negative regulation of glycolytic process	6/1882	14/18723	1.51e-03	1.64e-02	6
GO:00033001	Liver	NAFLD	cardiac muscle hypertrophy	20/1882	99/18723	1.80e-03	1.85e-02	20
GO:20003777	Liver	NAFLD	regulation of reactive oxygen species metabolic process	28/1882	157/18723	1.91e-03	1.93e-02	28
GO:00061402	Liver	NAFLD	regulation of nucleotide metabolic process	18/1882	86/18723	1.98e-03	1.98e-02	18
GO:19027436	Liver	NAFLD	regulation of lamellipodium organization	13/1882	54/18723	2.21e-03	2.14e-02	13
GO:19035787	Liver	NAFLD	regulation of ATP metabolic process	18/1882	87/18723	2.26e-03	2.19e-02	18
GO:0045912	Liver	NAFLD	negative regulation of carbohydrate metabolic process	12/1882	48/18723	2.30e-03	2.19e-02	12
GO:0010677	Liver	NAFLD	negative regulation of cellular carbohydrate metabolic process	11/1882	42/18723	2.32e-03	2.19e-02	11
GO:0014897	Liver	NAFLD	striated muscle hypertrophy	20/1882	102/18723	2.61e-03	2.41e-02	20
GO:00616146	Liver	NAFLD	pri-miRNA transcription by RNA polymerase II	13/1882	55/18723	2.64e-03	2.42e-02	13
GO:19027456	Liver	NAFLD	positive regulation of lamellipodium organization	10/1882	37/18723	2.82e-03	2.56e-02	10
GO:00148961	Liver	NAFLD	muscle hypertrophy	20/1882	104/18723	3.30e-03	2.93e-02	20
GO:19034094	Liver	NAFLD	reactive oxygen species biosynthetic process	14/1882	64/18723	3.95e-03	3.33e-02	14
GO:00709977	Liver	NAFLD	neuron death	52/1882	361/18723	5.08e-03	3.96e-02	52
GO:0006476	Liver	NAFLD	protein deacetylation	19/1882	101/18723	5.29e-03	4.09e-02	19

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa052032	Liver	HCC	Viral carcinogenesis	117/4020	204/8465	2.68e-03	8.98e-03	5.00e-03	117
hsa052033	Liver	HCC	Viral carcinogenesis	117/4020	204/8465	2.68e-03	8.98e-03	5.00e-03	117

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Cell-cell communication analysis

Identification of potential cell-cell interactions between two cell types and their ligand-receptor pairs for different disease states

Ligand

Receptor

LRpair

Pathway

Tissue

Disease Stage

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Single-cell gene regulatory network inference analysis

Find out the significant the regulons (TFs) and the target genes of each regulon across cell types for different disease states

Cell Type

Tissue

Disease Stage

Target Gene

RSS

Regulon Activity

∗The dot plots of a searched regulon are shown for all cell subpopulations in each disease state of each tissue based on the regulon specific score inferred using pySCENIC and by calculating the average expression.

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Somatic mutation of malignant transformation related genes

Annotation of somatic variants for genes involved in malignant transformation

Hugo Symbol

Variant Class

Variant Classification

dbSNP RS

HGVSc

HGVSp

HGVSp Short

SWISSPROT

BIOTYPE

SIFT

PolyPhen

Tumor Sample Barcode

Tissue

Histology

Sex

Age

Stage

Therapy Types

Drugs

Outcome

HDAC4

SNV

Missense_Mutation

novel

c.1009G>A

p.Glu337Lys

p.E337K

P56524

protein_coding

deleterious(0.01)

benign(0.231)

TCGA-5L-AAT1-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Hormone Therapy

letrozol

HDAC4

SNV

Missense_Mutation

rs753482334

c.2238N>A

p.Phe746Leu

p.F746L

P56524

protein_coding

deleterious(0.01)

benign(0.207)

TCGA-A2-A25A-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unspecific

Cytoxan

HDAC4

SNV

Missense_Mutation

c.2610N>G

p.Phe870Leu

p.F870L

P56524

protein_coding

deleterious(0)

probably_damaging(1)

TCGA-A8-A09G-01

Breast

breast invasive carcinoma

Female

>=65

III/IV

Unknown

HDAC4

SNV

Missense_Mutation

novel

c.1132N>G

p.Leu378Val

p.L378V

P56524

protein_coding

tolerated(0.3)

benign(0.001)

TCGA-AC-A5XS-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

femara

HDAC4

SNV

Missense_Mutation

c.2306G>A

p.Gly769Glu

p.G769E

P56524

protein_coding

deleterious(0.02)

benign(0.221)

TCGA-AN-A0FS-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HDAC4

deletion

Frame_Shift_Del

novel

c.887_909delNNNNNNNNNNNNNNNNNNNNNNN

p.Pro296GlnfsTer228

p.P296Qfs*228

P56524

protein_coding

TCGA-A7-A4SA-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

HDAC4

deletion

Frame_Shift_Del

novel

c.2626delG

p.Ala876LeufsTer81

p.A876Lfs*81

P56524

protein_coding

TCGA-D8-A27V-01

Breast

breast invasive carcinoma

Female

<65

I/II

Hormone Therapy

tamoxiphen

HDAC4

SNV

Missense_Mutation

novel

c.1090N>C

p.Ser364Pro

p.S364P

P56524

protein_coding

deleterious(0.04)

benign(0.001)

TCGA-C5-A8XJ-01

Cervix

cervical & endocervical cancer

Female

>=65

I/II

Chemotherapy

cisplatin

HDAC4

SNV

Missense_Mutation

rs745953691

c.412N>T

p.Arg138Cys

p.R138C

P56524

protein_coding

deleterious(0.02)

possibly_damaging(0.751)

TCGA-DG-A2KH-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

HDAC4

SNV

Missense_Mutation

rs753482334

c.2238N>A

p.Phe746Leu

p.F746L

P56524

protein_coding

deleterious(0.01)

benign(0.207)

TCGA-EK-A2IP-01

Cervix

cervical & endocervical cancer

Female

<65

I/II

Unknown

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Related drugs of malignant transformation related genes

Identification of chemicals and drugs interact with genes involved in malignant transfromation

(DGIdb 4.0)

Entrez ID	Symbol	Category	Interaction Types	Drug Claim Name	Drug Name	PMIDs
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME	inhibitor	CUDC-101	CUDC-101
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		APICIDIN	APICIDIN	19705846,17956988
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME	inhibitor	187051794
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		PMID29671355-Compound-62
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME	inhibitor	178103585	ROMIDEPSIN
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME	inhibitor	187051792	PANOBINOSTAT
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		BML-210	CHEMBL324053	16921367
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		PANOBINOSTAT	PANOBINOSTAT
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		PMID29671355-Compound-47a
9759	HDAC4	DRUGGABLE GENOME, CLINICALLY ACTIONABLE, TRANSCRIPTION FACTOR BINDING, TRANSCRIPTION FACTOR, ENZYME		BELINOSTAT	BELINOSTAT

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