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: HDAC6

Gene summary for HDAC6

Gene summary.

Gene information	Species	Human
	Gene symbol	HDAC6
	Gene ID	10013
	Gene name	histone deacetylase 6
	Gene Alias	CPBHM
	Cytomap	Xp11.23
	Gene Type	protein-coding
	GO ID	GO:0000209
	UniProtAcc	B4DZH6

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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
10013	HDAC6	NAFLD1	Human	Liver	NAFLD	3.21e-04	4.23e-01	-0.04
10013	HDAC6	S43	Human	Liver	Cirrhotic	1.62e-02	-8.46e-02	-0.0187
10013	HDAC6	HCC1_Meng	Human	Liver	HCC	3.41e-35	-4.38e-02	0.0246
10013	HDAC6	HCC2_Meng	Human	Liver	HCC	1.34e-04	-1.91e-02	0.0107
10013	HDAC6	HCC1	Human	Liver	HCC	4.10e-28	6.21e+00	0.5336
10013	HDAC6	HCC2	Human	Liver	HCC	1.85e-08	3.69e+00	0.5341
10013	HDAC6	S014	Human	Liver	HCC	3.31e-03	3.13e-01	0.2254
10013	HDAC6	S015	Human	Liver	HCC	3.50e-05	4.53e-01	0.2375
10013	HDAC6	S027	Human	Liver	HCC	7.37e-07	7.22e-01	0.2446
10013	HDAC6	S028	Human	Liver	HCC	6.13e-09	5.52e-01	0.2503
10013	HDAC6	S029	Human	Liver	HCC	3.47e-10	7.33e-01	0.2581

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Transcriptomic changes along malignancy continuum.

Tissue	Expression Dynamics	Abbreviation
Liver		HCC: Hepatocellular carcinoma
Liver		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:00485457	Liver	NAFLD	response to steroid hormone	75/1882	339/18723	3.44e-11	1.12e-08	75
GO:00165703	Liver	NAFLD	histone modification	90/1882	463/18723	5.74e-10	1.28e-07	90
GO:00713836	Liver	NAFLD	cellular response to steroid hormone stimulus	48/1882	204/18723	1.50e-08	1.83e-06	48
GO:00316477	Liver	NAFLD	regulation of protein stability	61/1882	298/18723	5.00e-08	4.71e-06	61
GO:00181055	Liver	NAFLD	peptidyl-serine phosphorylation	63/1882	315/18723	7.45e-08	6.60e-06	63
GO:00002095	Liver	NAFLD	protein polyubiquitination	51/1882	236/18723	1.04e-07	8.10e-06	51
GO:00305226	Liver	NAFLD	intracellular receptor signaling pathway	55/1882	265/18723	1.39e-07	1.03e-05	55
GO:00160495	Liver	NAFLD	cell growth	85/1882	482/18723	1.75e-07	1.25e-05	85
GO:00458617	Liver	NAFLD	negative regulation of proteolysis	66/1882	351/18723	4.02e-07	2.58e-05	66
GO:00182094	Liver	NAFLD	peptidyl-serine modification	64/1882	338/18723	4.65e-07	2.89e-05	64
GO:00069797	Liver	NAFLD	response to oxidative stress	78/1882	446/18723	7.85e-07	4.29e-05	78
GO:19029037	Liver	NAFLD	regulation of supramolecular fiber organization	66/1882	383/18723	8.97e-06	2.96e-04	66
GO:0018205	Liver	NAFLD	peptidyl-lysine modification	65/1882	376/18723	9.42e-06	3.02e-04	65
GO:00105065	Liver	NAFLD	regulation of autophagy	57/1882	317/18723	1.00e-05	3.18e-04	57
GO:00097556	Liver	NAFLD	hormone-mediated signaling pathway	39/1882	190/18723	1.15e-05	3.58e-04	39
GO:00485884	Liver	NAFLD	developmental cell growth	45/1882	234/18723	1.50e-05	4.38e-04	45
GO:00163585	Liver	NAFLD	dendrite development	43/1882	243/18723	1.70e-04	3.07e-03	43
GO:00434016	Liver	NAFLD	steroid hormone mediated signaling pathway	28/1882	136/18723	1.78e-04	3.14e-03	28
GO:00065153	Liver	NAFLD	protein quality control for misfolded or incompletely synthesized proteins	10/1882	28/18723	2.46e-04	4.09e-03	10
GO:00488133	Liver	NAFLD	dendrite morphogenesis	29/1882	146/18723	2.63e-04	4.26e-03	29

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Enriched KEGG pathways.

Pathway ID	Tissue	Disease Stage	Description	Gene Ratio	Bg Ratio	pvalue	p.adjust	qvalue	Count
hsa0501414	Liver	Cirrhotic	Amyotrophic lateral sclerosis	187/2530	364/8465	1.56e-18	6.50e-17	4.01e-17	187
hsa05203	Liver	Cirrhotic	Viral carcinogenesis	76/2530	204/8465	1.34e-02	4.20e-02	2.59e-02	76
hsa0501415	Liver	Cirrhotic	Amyotrophic lateral sclerosis	187/2530	364/8465	1.56e-18	6.50e-17	4.01e-17	187
hsa052031	Liver	Cirrhotic	Viral carcinogenesis	76/2530	204/8465	1.34e-02	4.20e-02	2.59e-02	76
hsa0501422	Liver	HCC	Amyotrophic lateral sclerosis	252/4020	364/8465	8.85e-18	7.41e-16	4.12e-16	252
hsa052032	Liver	HCC	Viral carcinogenesis	117/4020	204/8465	2.68e-03	8.98e-03	5.00e-03	117
hsa0501432	Liver	HCC	Amyotrophic lateral sclerosis	252/4020	364/8465	8.85e-18	7.41e-16	4.12e-16	252
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

TF	Cell Type	Tissue	Disease Stage	Target Gene	RSS	Regulon Activity
HDAC6	MYOFIB	Colorectum	ADJ	OTUD6B-AS1,COL13A1,RNF170, etc.	3.26e-01
HDAC6	MYOFIB	Colorectum	FAP	OTUD6B-AS1,COL13A1,RNF170, etc.	2.54e-01
HDAC6	BAS	Endometrium	ADJ	MINDY2,ZNF662,TAF1C, etc.	6.21e-03
HDAC6	iATC	Thyroid	Healthy	MRPL36,NSRP1,MVB12A, etc.	6.35e-02

∗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

HDAC6

SNV

Missense_Mutation

novel

c.3579G>C

p.Gln1193His

p.Q1193H

Q9UBN7

protein_coding

deleterious(0)

possibly_damaging(0.722)

TCGA-A7-A6VW-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

doxorubicin

HDAC6

SNV

Missense_Mutation

c.2601N>A

p.Met867Ile

p.M867I

Q9UBN7

protein_coding

tolerated(0.2)

benign(0.003)

TCGA-AC-A23H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HDAC6

SNV

Missense_Mutation

rs782451640

c.2609G>A

p.Arg870Gln

p.R870Q

Q9UBN7

protein_coding

tolerated(0.48)

benign(0.033)

TCGA-AN-A046-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Unknown

HDAC6

SNV

Missense_Mutation

c.1699N>T

p.Asp567Tyr

p.D567Y

Q9UBN7

protein_coding

deleterious(0)

probably_damaging(0.914)

TCGA-AO-A0J5-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Other, specify in notesBisphosphonate

zoledronic

HDAC6

SNV

Missense_Mutation

c.379C>G

p.Arg127Gly

p.R127G

Q9UBN7

protein_coding

deleterious(0)

possibly_damaging(0.773)

TCGA-AQ-A04J-01

Breast

breast invasive carcinoma

Female

<65

I/II

Chemotherapy

cytoxan

HDAC6

SNV

Missense_Mutation

c.2518N>C

p.Glu840Gln

p.E840Q

Q9UBN7

protein_coding

deleterious(0.03)

benign(0.113)

TCGA-AR-A0TX-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HDAC6

SNV

Missense_Mutation

c.846N>T

p.Arg282Ser

p.R282S

Q9UBN7

protein_coding

tolerated(0.77)

benign(0.038)

TCGA-AR-A24H-01

Breast

breast invasive carcinoma

Female

>=65

I/II

Hormone Therapy

tamoxiphen

HDAC6

SNV

Missense_Mutation

novel

c.208N>A

p.Gly70Arg

p.G70R

Q9UBN7

protein_coding

deleterious(0.03)

benign(0.294)

TCGA-BH-A0BZ-01

Breast

breast invasive carcinoma

Female

<65

III/IV

Chemotherapy

doxorubicin

HDAC6

SNV

Missense_Mutation

rs781974625

c.3181N>A

p.Glu1061Lys

p.E1061K

Q9UBN7

protein_coding

tolerated(0.35)

benign(0)

TCGA-C8-A12P-01

Breast

breast invasive carcinoma

Female

<65

I/II

Unknown

HDAC6

SNV

Missense_Mutation

rs782618133

c.2021N>G

p.Tyr674Cys

p.Y674C

Q9UBN7

protein_coding

deleterious(0)

probably_damaging(0.989)

TCGA-E9-A5FL-01

Breast

breast invasive carcinoma

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
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PMID28092474-Compound-32i
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PMID29671355-Compound-28
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PMID29671355-Compound-9
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PMID29671355-Compound-14
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PRACINOSTAT	PRACINOSTAT
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		PMID28092474-Compound-33p
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME		BELINOSTAT	BELINOSTAT	25937017
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME	inhibitor	187051807	SCRIPTAID
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME	inhibitor	187051792	PANOBINOSTAT
10013	HDAC6	ENZYME, TRANSCRIPTION FACTOR, TRANSCRIPTION FACTOR BINDING, DRUGGABLE GENOME	inhibitor	249565599

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