Aims:　Colorectal　cancer　(CRC)　is　the　fourth　leading　cause　of　cancer-related　mortality　worldwide.　Over-expression　of　tetraspanin　8　(TSPAN8)　is　related　to　the　development　and　progression　of　CRC.　Whether　TSPAN8　plays　a　role　in　the　growth　of　colorectal　cancer　and　its　epigenetic　mechanisms　regulated　by　Lysine　Specific　Demethylase　1　(LSD1)　are　still　unknown.　Main　methods:　In　this　study,　RT-PCR　and　western　blotting　were　used　to　analyze　the　mRNA　and　protein　expression,　respectively;　cell　viability　was　assayed　with　MTS　analysis;　cell　migration　was　measured　with　Trans-well　analysis.　Key　findings:　In　the　present　study,　the　results　indicated　that　the　mRNA　levels　of　LSD1　and　TSPAN8　in　CRC　were　significantly　higher　than　that　in　corresponding　adjacent　non-tumor　tissue.　Down-regulation　of　LSD1　or　TSPAN8　as　well　as　LSD1　inhibitor　Tranylcypromine　hemisulfate　inhibited　the　proliferation　and　migration　of　CRC　cells,　while　over-expression　of　LSD1　exhibited　opposite　effects.　LSD1　up-regulated　TSPAN8　expression　and　reduced　H3K9me2　occupancy　on　the　TSPAN8　promoter　in　CRC　cells.　TSPAN8　promoted　epithelial-mesenchymal　transition　(EMT)　in　CRC　cells　in　LSD1-dependent　manner.　Significance:　TSPAN8　may　be　considered　as　a　promising　biomarker　for　the　diagnosis　and　prognosis　in　patients　with　CRC.　Furthermore,　TSPAN8　could　be　a　novel　therapeutic　target　and　potent　LSD1　inhibitors　could　be　designed　and　developed　in　the　treatment　of　CRC.